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1.
Hemasphere ; 8(4): e63, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38566804

RESUMO

Circulating tumor plasma cells (CTPCs) provide a noninvasive alternative for measuring tumor burden in newly diagnosed multiple myeloma (NDMM). Moreover, measurable residual disease (MRD) assessment in peripheral blood (PBMRD) can provide an ideal alternative to bone marrow MRD, which is limited by its painful nature and technical challenges. However, the clinical significance of PBMRD in NDMM still remains uncertain. Additionally, data on CTPC in NDMM patients not treated with transplant are scarce. We prospectively studied CTPC and PBMRD in 141 NDMM patients using highly sensitive multicolor flow cytometry (HS-MFC). PBMRD was monitored at the end of three cycles (PBMRD1) and six cycles (PBMRD2) of chemotherapy in patients with detectable baseline CTPC. Patients received bortezomib-based triplet therapy and were not planned for an upfront transplant. Among baseline risk factors, CTPC ≥ 0.01% was independently associated with poor progression-free survival (PFS) (hazard ratio [HR] = 2.77; p = 0.0047) and overall survival (OS) (HR = 2.9; p = 0.023) on multivariate analysis. In patients with detectable baseline CTPC, undetectable PBMRD at both subsequent time points was associated with longer PFS (HR = 0.46; p = 0.0037), whereas detectable PBMRD at any time point was associated with short OS (HR = 3.25; p = 0.004). Undetectable combined PBMRD (PBMRD1 and PBMRD2) outperformed the serum-immunofixation-based response. On multivariate analysis, detectable PBMRD at any time point was independently associated with poor PFS (HR = 2.0; p = 0.025) and OS (HR = 3.97; p = 0.013). Thus, our findings showed that CTPC and PBMRD assessment using HS-MFC provides a robust, noninvasive biomarker for NDMM patients not planned for an upfront transplant. Sequential PBMRD monitoring has great potential to improve the impact of the existing risk stratification and response assessment models.

2.
Indian J Med Res ; 159(2): 193-205, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38577858

RESUMO

BACKGROUND OBJECTIVES: The role of consolidation radiation therapy (CRT) after complete metabolic response to chemotherapy in advanced-stage (stage III and IV) Hodgkin lymphoma (HL) is controversial. This study was undertaken to assess the clinical outcomes in terms of event free survival, local failure free survival and overall survival in individuals with advanced HL treated with chemotherapy and CRT. METHODS: A retrospective review was conducted to study the long-term clinical outcomes in individuals diagnosed with HL and treated with chemotherapy and CRT from 2012 to 2016 at a tertiary cancer care hospital in India. RESULTS: Data from 203 study participants with advanced-stage HL were analyzed. Positron emission tomography-computed tomography (PET-CT) was done at baseline and after 2 cycles for response assessment. The median age at presentation was 32 yr [interquartile range (IQR): 26-46]. Early metabolic response (after 2 cycles) and delayed metabolic response (after 4 or 6 cycles) were observed in 74.4 and 25.6 per cent of individuals, respectively. With a median follow up of 52 months (IQR: 40-67), the five-year event-free survival (EFS), local failure-free survival (LFFS) and overall survival (OS) were 83.2, 95.1 and 94.6 per cent, respectively. On univariate analysis, extranodal disease was associated with inferior EFS (P=0.043). Haemoglobin <10.5 g/dl (P=0.002) and Hasenclever index >3 (P=0.00047) were associated with poorer OS. Relapses were observed in 28/203 (13.8%) study participants with predominance at central nodal stations. The median time to relapse was 19.4 months (IQR: 13-33). Local relapse alone (at the irradiated site) was observed in 5/28 study participants, systemic (distant) relapse in 14/28 individuals, while both systemic and local relapse was observed in 9/28 participants. Extranodal disease (P=0.05), bulky disease (P=0.005) and haemoglobin concentration ≤10.5 g/dl (P=0.036) were significant predictors for disease relapse. INTERPRETATION CONCLUSIONS: Individuals with advanced-stage HL treated with anthracycline-based chemotherapy (anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine regimen) and CRT had excellent long-term outcomes. As isolated infield failures are uncommon, selective consolidation with conformal RT to high-risk sites improves final disease outcomes.


Assuntos
Doença de Hodgkin , Humanos , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Estudos Retrospectivos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Dacarbazina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Terapia Combinada , Doxorrubicina , Recidiva , Hemoglobinas , Estadiamento de Neoplasias , Resultado do Tratamento
3.
Cancers (Basel) ; 16(4)2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38398081

RESUMO

Hodgkin lymphomas are radiosensitive and curable tumors that often involve the mediastinum. However, the application of radiation therapy to the mediastinum is associated with late effects including cardiac and pulmonary toxicities and secondary cancers. The adoption of conformal IMRT and deep inspiration breath- hold (DIBH) can reduce the dose to healthy normal tissues (lungs, heart and breast). We compared the dosimetry of organs at risk (OARs) using different IMRT techniques for two breathing conditions, i.e., deep inspiration breath hold (DIBH) and free breathing. Twenty-three patients with early-stage mediastinal Hodgkin lymphomas were accrued in the prospective study. The patients were given treatment plans which utilized full arc volumetric modulated arc therapy (F-VMAT), Butterfly VMAT (B-VMAT), and fixed field IMRT (FF-IMRT) techniques for both DIBH and free breathing methods, respectively. All the plans were optimized to deliver 95% of the prescription dose which was 25.2 Gy to 95% of the PTV volume. The mean dose and standard error of the mean for each OAR, conformity index (CI), and homogeneity index (HI) for the target using the three planning techniques were calculated and compared using Student's t-test for parametric data and Wilcoxon signed-rank test for non-parametric data. The HI and CI of the target was not compromised using the DIBH technique for mediastinal lymphomas. The mean values of CI and HI for both DIBH and FB were comparable. The mean heart doses were reduced by 2.1 Gy, 2.54 Gy, and 2.38 Gy in DIBH compared to FB for the F-VMAT, B-VMAT, and IMRT techniques, respectively. There was a significant reduction in V5Gy, V10Gy, and V15Gy to the heart (p < 0.005) with DIBH. DIBH reduced the mean dose to the total lung by 1.19 Gy, 1.47 Gy, and 1.3 Gy, respectively. Among the 14 female patients, there was a reduction in the mean right breast dose with DIBH compared to FB (4.47 Gy vs. 3.63 Gy, p = 0.004). DIBH results in lower heart, lung, and breast doses than free breathing in mediastinal Hodgkin Lymphoma. Among the different IMRT techniques, FF-IMRT, B-VMAT, and F-VMAT showed similar PTV coverage, with similar conformity and homogeneity indices. However, the time taken for FF-IMRT was much longer than for the F-VMAT and B-VMAT techniques for both breathing methods. B-VMAT and F-VMAT emerged as the optimal planning techniques able to achieve the best target coverage and lower doses to the OARs, with less time required to deliver the prescribed dose.

4.
Cell Transplant ; 33: 9636897241226573, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38258793

RESUMO

Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo. WSE is currently under clinical investigation for the prevention and treatment of aGvHD.


Assuntos
Doença Enxerto-Hospedeiro , Leucemia , Withania , Síndrome da Liberação de Citocina , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Leucemia/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
5.
Int J Hematol ; 119(1): 71-79, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37952243

RESUMO

Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity and outcomes between two RIC regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), retrospectively over a 10-year period in two donor groups, matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. The study included 138 patients, of which 105 received MRD/MUD (Flu-Mel: 94, Flu-Treo: 11) and 33 Haplo (Flu-Mel: 17, Flu-Treo: 16) transplants. In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo (P = 0.02). Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%; P = 0.039), but not the MRD/MUD group. Median follow-up time for all patients was 4.8 years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 53% with Flu-Treo (P = 0.0694). Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Melfalan/efeitos adversos , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Vidarabina , Doadores não Relacionados , Condicionamento Pré-Transplante , Diarreia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle
7.
Blood Cell Ther ; 6(3): 95-103, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-38146353

RESUMO

Background: The prognosis of Hodgkin lymphoma (HL) relapsing post autologous transplant (AuSCT) is poor. Even with novel therapies, only approximately 20%-25% of patients attain complete remissions, with a median progression-free survival (PFS) of approximately 5-15 months. Lenalidomide has been shown to have activity in relapsed HL. We retrospectively analyzed the outcomes of patients with relapsed HL post AuSCT treated with lenalidomide alone or in combination with dexamethasone at our center. Patients and methods: Records of 143 patients transplanted from November 2007 to October 2021 were reviewed. Of these patients, 41 (28%) relapsed, and 16 (39%) received lenalidomide alone or in combination with dexamethasone. Data collected included demographic, pathological, staging, and prior therapy details. Lenalidomide was administered at 10-25 mg/day on an intermittent or continuous schedule alone or in combination with dexamethasone (20-40 mg weekly). Response was assessed using PET-CT scan in accordance with Lugano criteria. Standard definitions were used for response, PFS, and overall survival (OS). Toxicities were graded using Common Terminology Criteria for Adverse Events version 5.0. Statistical analysis was done using SPSS Version 21. Results: The median age of the patients was 25.5 years, and 10 were males. Eleven (69%) had advanced disease, and 7 (44%) were refractory to last systemic therapy. Nine patients received lenalidomide alone and 7 with dexamethasone. Four (25%) had complete response, and another four (25%) had partial response, with an overall response rate of 50%. The 3-year PFS and OS were 31% and 38%, respectively. Grade III/IV toxicities were only hematological, neutropenia and thrombocytopenia in four and three patients, respectively. No therapy-related deaths were recorded. Conclusions: Lenalidomide alone or in combination with dexamethasone is a safe and effective therapy for relapsed HL post AuSCT and results in durable response and long-term survival in approximately one-third of the patients. However, these results needs verification in larger prospective studies.

8.
Int Immunopharmacol ; 125(Pt A): 111054, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37890379

RESUMO

BACKGROUND: We had previously reported significant association of immunoectoenzyme CD26 expression on donor harvest with acute Graft-versus-Host-Disease (aGVHD) in allogeneic stem cell transplantation (ASCT) patients. The current study was aimed at analysing CD26 signaling pathway molecules and understanding their impact on immune reconstitution and clinical outcomes post-ASCT. SUBJECTS AND METHODOLOGY: The study cohort included 26 transplant donors/patients who underwent reduced intensity (n = 21), myeloablative (n = 4) and non-myeloablative (n = 1) ASCT for hematological malignancies. Donors were matched related donors (n = 19) and haploidentical donors (n = 7). Surface expression of CD26, CD73 and ADA, and various immune cell subtypes were assessed by multicolour-flow cytometry. Soluble CD26 (sCD26) and cytokine levels were measured in plasma samples by ELISA and Multiplex Luminex assay, respectively. Immune cells from healthy individuals were stimulated with phytohemagglutinin (PHA) in the presence or absence of CD26 inhibitor. Effect of CD26 inhibition on NF-κB localization in PHA stimulated cells was analysed by immunofluorescence and confocal microscopy. Pro-inflammatory cytokines from the culture supernatants were detected with Cytometric bead array flow cytometry. Association of all measured markers with clinical outcomes was evaluated using appropriate statistical tests. RESULTS: CD26 surface expression on PBSC donor harvest cells showed increased risk of chronic GVHD (cGVHD, p = 0.055). Amongst the various immune cell subtypes, decreased B cells in harvest showed significant association with aGVHD (p = 0.022) whereas increased myeloid dendritic cells and CD3+T cells at Day100 in peripheral blood of transplant recipients correlated with cGVHD (p = 0.046) and aGVHD (p = 0.035), respectively. Further, high sCD26 in transplant recipients at Day100 exhibited association with reduced event-free survival (EFS) (p = 0.011). Higher CD26 expression on more & less mature NK cells, naïve & post-switched memory B cells and Treg cells in the donor harvest (p < 0.05) led to lower EFS in transplant recipients. Mechanistically, CD26 inhibitor caused dose-dependent reduction in CD26 enzyme activity and in pro-inflammatory cytokine production in post mitogen-stimulated T cell cultures. CONCLUSION: Our study has implicated that lower CD26 expression on immune cell subtypes of the donor stem cell harvest is associated with reduced risk of GVHD and better survival. The underlying mechanism was found to be through NF-κB pathway and pro-inflammatory cytokines. Based on these observations, chemically designed or natural resources-based CD26 inhibitors can be explored further in clinical trials for improving ASCT outcomes.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , NF-kappa B , Dipeptidil Peptidase 4 , Citocinas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doadores de Tecidos
9.
Transplant Cell Ther ; 29(12): 777.e1-777.e8, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37678607

RESUMO

Long-term cryopreservation of peripheral blood stem cells (PBSCs) is highly useful in the setting of tandem/multiple transplantations or treatment of relapse in the autologous hematopoietic stem cell transplantation (HSCT) setting. Even in allogeneic HSCT, donor lymphocyte infusions may be stored for months to years if excess stem cells are collected from donors. Cryopreservation is a delicate, complex, and costly procedure, and higher concentrations of dimethyl sulfoxide (DMSO), a commonly used cryoprotectant, can be toxic to cells and cause adverse effects in the recipient during infusions. In this study, we examined the effect of long-term cryopreservation using 4.35% DMSO (as final concentration) with methyl cellulose and uncontrolled rate freezing in a mechanical freezer (-80 °C) on the viability and colony-forming ability of CD34+ human PBSCs. For patients undergoing autologous HSCT, PBSCs were cryopreserved using DMSO (final concentration of 4.35%) with methyl cellulose. The post-thaw viability of PBSCs was determined using Trypan blue exclusion and flow cytometry-based 7-amino-actinomycin-D (FC-7AAD) methods. Concentrations of CD34+ stem cells and immune cell subsets in post-thaw PBSC harvest samples were assessed using multicolor flow cytometry, and the clonogenic potential of post-thaw stem cells was studied using a colony-forming unit (CFU) assay. CD34+ stem cell levels were correlated with the prestorage CD34 levels using the Pearson correlation test. The viability results in the Trypan blue dye exclusion method and the flow cytometry-based method were compared using Bland-Altman plots. We studied 26 PBSC harvest samples with a median cryopreservation duration of 6.6 years (range, 3.8 to 11.5 years). The median viability of post-thaw PBSCs was >80% using both methods, with a weak agreement between them (r = .03; P = .5). The median CD34+ stem cell count in the post-thaw samples was 9.13 × 106/kg (range, .44 to 26.27 × 106/kg). The CFU assay yielded a good proliferation and differentiation potential in post-thaw PBSCs, with a weak correlation between granulocyte macrophage CFU and CD34+ stem cell levels (r = .4; P = .05). Two samples that had been cryopreserved for >8 years showed low viability. Cryopreservation of PBSCs using 4.35% DMSO with methyl cellulose and uncontrolled freezing in a mechanical freezer at -80 °C allows the maintenance of long-term viability of PBSC for up to 8 years.


Assuntos
Dimetil Sulfóxido , Células-Tronco de Sangue Periférico , Humanos , Congelamento , Dimetil Sulfóxido/farmacologia , Células-Tronco Hematopoéticas , Metilcelulose/farmacologia , Região de Recursos Limitados , Azul Tripano/farmacologia , Criopreservação/métodos , Antígenos CD34/farmacologia
10.
Transpl Immunol ; 81: 101925, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37648032

RESUMO

BACKGROUND: In hematopoietic stem cell transplant (HSCT), vitamin D deficiency has been variably associated with increased complications, primarily graft versus host disease (GvHD), with a potential impact on survival. Results from various studies however, have not been consistent. This analysis was conducted to study the impact of peri-transplant vitamin D levels on transplant outcomes in patients with acute leukemia (AL) who underwent HLA matched (related/unrelated) HSCT. METHODS: This was a single center retrospective study. Patients of AL including Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML) or Mixed Phenotypic Acute Leukemia (MPAL) who underwent fully matched or 9/10 transplants (related/unrelated) between 2008 and 2019 were included. Vitamin D deficiency was defined as serum 25-hydroxy vitamin D3 levels ≤20 ng/ml. Those with deficiency received replacement with oral vitamin D at a dose of 60,000 IU weekly for 8 weeks followed by maintenance with daily vitamin D (800 IU/day). Vitamin D levels were repeated at 4 months from start of replacement. For patients who received correction, repeat levels >20 ng/ml were considered replete. Based on vitamin D levels in the peri-transplant period (within 120 days of transplant), patients were categorised as either vitamin D replete (> 20 ng/ml) or deplete (≤ 20 ng/ml). Peri-transplant vitamin D status was correlated with transplant outcomes. RESULTS: Of the 133 patients included, 31 were deplete (median vitamin D 15.0 ng/ml) and 102 were replete (median vitamin D 34 ng/ml) at time of transplant. Both groups were matched for age, diagnosis, EBMT score and disease risk index (DRI). There were no differences in time to neutrophil or platelet engraftment, CMV reactivation, acute GvHD (aGvHD) or chronic GvHD (cGvHD) between the two groups. Relapse rate, Progression Free Survival (PFS) and Overall Survival (OS) were also comparable between the 2 groups. CONCLUSION: The incidence of vitamin D deficiency was high in our patient cohort. Patients who were vitamin D deficient at the time of transplant did not have inferior outcomes, suggesting a limited role of vitamin D in influencing transplant outcomes.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Deficiência de Vitamina D , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Vitamina D/uso terapêutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/etiologia , Doença Aguda , Transplante de Células-Tronco , Condicionamento Pré-Transplante/métodos
11.
Int Immunopharmacol ; 121: 110437, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37311352

RESUMO

Acute graft versus host disease (aGvHD) contributes to a significant proportion of non-relapse mortality and morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Withaferin-A (WA), a phytomolecule obtained from Withania somnifera (Ashwagandha), is known to have anti-inflammatory, anti-proliferative and immunomodulatory properties. The efficacy of WA for the prevention and treatment of aGvHD was evaluated using a murine model of alloHSCT. Prophylactic administration of WA to mice mitigated the clinical symptoms of aGvHD and improved survival significantly compared to the GvHD control [HR = 0.07 (0.01-0.35); P < 0.001]. Furthermore, WA group had better overall survival compared to standard prophylactic regimen of CSA + MTX [HR = 0.19 (0.03-1.1), P < 0.05]. At the same time, WA did not compromise the beneficial GvL effect. In addition, WA administered to animals after the onset of aGvHD could reverse the clinical severity and improved survival, thus establishing its therapeutic potential. Our findings suggest that WA reduced the systemic levels of Th1, Th2 and Th17 inflammatory cytokine and increased the anti-inflammatory cytokine IL-10 levels significantly (P < 0.05). WA also inhibited lymphocytes migration to gut, liver, skin and lung and protected these organs from damage. Ex-vivo, WA inhibited proliferation of human peripheral blood mononuclear cells (hPBMCs), modulated immune cell phenotype and decreased cytokine release. In addition, WA inhibited pJAK2 and pSTAT3 protein levels in mouse splenocytes and hPBMCs. In conclusion, our study demonstrates the utility of WA for the prevention and treatment of aGvHD, which should be further evaluated in a clinical setting.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Humanos , Animais , Camundongos , Efeito Enxerto vs Leucemia , Leucócitos Mononucleares , Citocinas/uso terapêutico , Leucemia/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Doença Aguda
12.
Indian J Hematol Blood Transfus ; 39(1): 40-49, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36699432

RESUMO

Outcomes with DLI alone for post-transplant relapsed hematological malignancies are poor especially in acute leukemias. Addition of immunomodulatory drugs to DLI may augment GVL effect. Use of lenalidomide with DLI to augment GVL has not been previously reported. This retrospective analysis was to compare the outcomes of DLI with or without lenalidomide. All consecutive patients who received DLI from 01/2010 through 01/2020 were included. DLIs were given without any immunosuppression. Lenalidomide, when used, was given continuously, starting with 1st or subsequent DLI. Patients who received lenalidomide were compared with those who did not. Event (hematological relapse or death) free survival (EFS) and overall survival (OS) were calculated from 1st DLI. Primary objective was to compare OS. Secondary objectives were EFS, CR rates, acute GVHD, lenalidomide toxicities and DLI related mortality (TRM). Total 61 patients received DLI-43 without and 18 with lenalidomide; all outcomes in the 2 groups were similar. There were 26 patients with HLA-A*24 and/or HLA-B*40. Among these, trend towards improvement in OS (median OS not reached vs. 8 months, 4 year OS was 62% vs. 32%, p = 0.1) and EFS (median 9 vs. 1 month, 4 year EFS 50% vs. 22%, p = 0.1) was seen with lenalidomide. Overall, there was no improvement in outcomes by adding lenalidomide to DLI. However, among patients with HLA*24 or B*40, there was a trend to improved survival with lenalidomide. Use of lenalidomide to augment the GVL effect of DLI warrants further exploration.

13.
Indian J Hematol Blood Transfus ; 39(1): 50-56, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36699439

RESUMO

Relationship between various combinations of KIR ligands and HLA alleles have been studied in several diseases. The aim of this retrospective study was to estimate the frequency of HLA alleles and KIR ligands among acute myeloid leukemia patients and healthy controls in order to examine the possible association of HLA alleles and KIR ligands with AML. A total of 439 acute myeloid leukemia patients and 1317 unrelated, healthy ethnic Indian controls were included in the study. HLA typing was performed using PCR-SSP. KIR ligands were assigned by using the KIR ligand Calculator. The frequency of HLA alleles and KIR ligands in patients was then compared with the controls. As compared to controls, frequencies of HLA-A*03 and HLA-B*35 were increased in AML patients, whereas, that of HLA-C*03 was decreased. Frequencies of HLA-A*03 and HLA-C*15 were increased in male patients, however, no significant difference was observed in female patients as compared to controls. In the pediatric group, the frequencies of HLA-A*01 was decreased and that of HLA-A*03 and HLA-B*18 were increased, whereas, frequencies of HLA-B*13 was decreased and that of HLA-B*27 was increased in the adult patients. In the haplotype analysis, the frequency of HLA-A*24/B*35/DRB1*15 was increased in overall patients. In adult group, the frequency of HLA-A*01/B*44/DRB1*07 was increased in patients than in controls. No significant association was observed between KIR ligands and susceptibility/ protection to AML. Our results indicate that certain HLA alleles and haplotypes have presumptive positive or negative role in conferring protection/susceptibility to AML. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01550-0.

14.
Indian J Hematol Blood Transfus ; 39(1): 57-70, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36699441

RESUMO

Primary CNS lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma with the worst outcomes amongst all extranodal lymphomas. There is a scarcity of data on real-world outcomes of primary CNS lymphoma (PCNSL) owing to the rarity of the disease. This study analyzed the demographic patterns, risk stratification, treatment regimens used, & outcomes of patients treated at Tata Memorial Center Mumbai, India. This is a retrospective analysis of newly diagnosed primary CNS lymphoma patients treated at our centre over seven years from January 2013 to December 2019. A total of 142 patients with PCNSL were diagnosed during this period. Thirty (21.1%) patients were deemed ineligible for any systemic or local therapies,ten patients were referred to other hospitals, two patients had relapsed disease, and one was excluded because age less than 18 years. Finally 99 patients were included in the final analysis. Among these 99 patients,72 patients (72.7%) were < 60 years,70 (70.7%) patients had Eastern cooperative oncology group (ECOG) performance status (PS) less than equal to 2. DLBCL was the most common histology (86.4%) while rests were high grade B cell NHL NOS (11.4%),Burkitt's Lymphoma(1%),Peripheral T-cell Lymphoma NOS (1.2%). Only one of 99 patients was positive for HIV serology. Multiple intracranial lesions were found in 59.5%. Surgical resection was performed in 28.4% of patients. Out of 63 patients in whom the International extranodal lymphoma study group (IELSG) score is available, 34(54%) were IELSG high-risk groups. As per Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping, patients were almost equally distributed in all the risk groups, with 32(32.3%) patients in risk group 1 (age < 50 years), 36(36.4%) patients in risk group 2 (age > 50 years, KPS > = 70), and 31(31.3%) patients in risk group 3 age > 50 years, KPS < 70). First-line treatment with high dose methotrexate (HD-MTX) based regimens was administered to 92 (92.9%) patients, and 72.8% of these patients received rituximab. Of these 92 patients, 59 (64.1%) patients could complete induction, and 52 patients received consolidation. Thirty-one patients received high dose cytarabine based chemo consolidation, one patient underwent high dose chemotherapy followed by autologous stem cell transplantation (ACST), and 19 patients received whole-brain radiotherapy (WBRT) and 1 patient received temozolomide as consolidation regimen. Thus only 52 patients completed the entire course of induction with consolidation therapy. The response to treatment was assessed using International PCNSL Collaborative Group Criteria. Post completion of consolidation, 49(94.2%) patients had a complete response. With a median follow-up duration of 39.2 months, the median progression-free survival (PFS) and the median overall survival (OS) of the patients taken into the analysis (N = 99) were 21 and 37 months respectively. On multivariate analysis, age < 60 yrs, > = 5 HD-MTX cycles received & the use of rituximab predicted better OS.Outcomes of patients with PCNSL treated with HD-MTX based therapy are comparable to reported literature however a large proportion of patients do not undergo required treatment despite the curable nature of disease. Supplementary Information: The online version supplementary material available at 10.1007/s12288-022-01557-7.

16.
Int J Clin Pract ; 2022: 2449068, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685574

RESUMO

Background: This manuscript describes the genetic features of SARS-CoV-2 mutations, prevalent phylogenetic lineages, and the disease severity amongst COVID-19-vaccinated individuals in a tertiary cancer hospital during the second wave of the pandemic in Mumbai, India. Methods: This observational study included 159 COVID-19 patients during the second wave of the pandemic from 17th March to 1st June 2021 at a tertiary cancer care centre in Mumbai. The cohort comprised of healthcare workers, staff relatives, cancer patients, and patient relatives. For comparison, 700 SARS-CoV-2 genomes sequenced during the first wave (23rd April to 25th September 2020) at the same centre were also analysed. Patients were assigned to nonvaccinated (no vaccination or <14 days from the 1st dose, n = 92), dose 1(≥14 days from the 1st dose to <14 days from the 2nd dose, n = 29), and dose 2 (≥14 days from the 2nd dose, n = 38) groups. Primary measure was the prevalence of SARS-CoV-2 genomic lineages among different groups. In addition, severity of COVID-19 was assessed according to clinical and genomic variables. Results: Kappa B.1.1671.1 and delta B.1.617.2 variants contributed to an overwhelming majority of sequenced genomes (unvaccinated: 40/92, 43.5% kappa, 46/92, 50% delta; dose 1: 14/29, 48.3% kappa, 15/29, 51.7% delta; and dose 2: 23/38, 60.5% kappa, 14/38 36.8% delta). The proportion of the kappa and delta variants did not differ significantly across the unvaccinated, dose 1, and dose 2 groups (p = 0.27). There was no occurrence of severe COVID-19 in the dose 2 group (0/38, 0% vs. 14/121, 11.6%; p = 0.02). SARS-CoV-2 genomes from all three severe COVID-19 patients in the vaccinated group belonged to the delta lineage (3/28, 10.7% vs. 0/39, 0.0%, p = 0.04). Conclusions: Sequencing analysis of SARS-COV-2 genomes from Mumbai during the second wave of COVID-19 suggests the prevalence of the kappa B.1.617.1 and the delta B.1.627.2 variants among both vaccinated and unvaccinated individuals. Continued evaluation of genomic sequencing data from breakthrough COVID-19 is necessary for monitoring the properties of evolving variants of concern and formulating appropriate immune response boosting and therapeutic strategies.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/prevenção & controle , ChAdOx1 nCoV-19 , Genômica , Humanos , Filogenia , SARS-CoV-2/genética
17.
Eur J Clin Pharmacol ; 78(8): 1321-1330, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35652931

RESUMO

PURPOSE: Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. METHODS: Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. RESULTS: Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. CONCLUSION: Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.


Assuntos
Antineoplásicos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/farmacocinética , Citocromo P-450 CYP3A/genética , Humanos , Mesilato de Imatinib/farmacocinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único
18.
Cell Transplant ; 31: 9636897221086969, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35435039

RESUMO

Mucositis is nearly inevitable following high-dose chemotherapy. Several pro-inflammatory cytokines play a role in pathogenesis of mucositis. Curcumin inhibits inflammatory cytokines through inhibition of nuclear factor kappa-ß. We studied the effects of curcumin on the acute toxicities and inflammatory cytokines following melphalan (200 mg/m2) for autologous hematopoietic stem cell transplantation (HSCT) for myeloma. The control group (first 10 enrolled patients who received standard supportive care) was compared with curcumin group (next 30 patients who received chewable curcumin lozenges, 4 g twice daily from 2 days before melphalan till day +28 along with standard supportive care). The toxicities were recorded as per World Health Organization (WHO) criteria and CTCAE v3.0 as applicable. Cytokine profiling was done in both groups at similar time points. In the curcumin group, there was significant decrease in grade 3/4 vomiting (3% vs 40%, P = 0.01) and total parenteral nutrition use (47% vs 90%, P = 0.026). Grade 3/4 mucositis (43% vs 60%) and diarrhea (33% vs 70%) were also less, but not statistically significant. This coincided with 3.2-fold lower area under the concentration time curve (AUC) of IL-8 from day -3 to day 14 in curcumin group compared with control group (P = 0.039). We conclude that curcumin mitigates toxicities of high-dose melphalan, possibly through IL-8 modulation. Randomized studies are warranted to explore benefits of curcumin in HSCT.


Assuntos
Curcumina , Transplante de Células-Tronco Hematopoéticas , Mucosite , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Interleucina-8 , Melfalan/efeitos adversos , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo
19.
PLoS One ; 17(2): e0262212, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35120140

RESUMO

BACKGROUND: Transplant related toxicity is a major therapeutic challenge. We have previously reported that the toxicity of chemotherapy is largely not directly because of the drugs themselves; rather it is mainly due to DNA damage, apoptosis and hyper-inflammation triggered by cell-free chromatin particles that are released because of drug-induced host cell death. Cell-free chromatin particles can be inactivated by free-radicals which are generated when the nutraceuticals resveratrol and copper are administered orally. We investigated if a combination of resveratrol and copper would reduce transplant related toxicities in an exploratory, prospective dose-escalation study. PATIENTS AND METHODS: Twenty-five patients with multiple myeloma were enrolled between March 2017 to August 2019. Patients were divided into 3 groups: control (Group 1, N = 5) received vehicle alone; group 2 (N = 15) received resveratrol-copper at dose level I (resveratrol = 5.6 mg and copper = 560 ng); group 3 (N = 5) received resveratrol-copper at dose level II (resveratrol = 50 mg and copper = 5 µg). The dose was given twice daily with the first dose administered 48 hours before administering melphalan and continued until day +21 post-transplant. Common Terminology Criteria for Adverse Events version 4.02 was used to assess toxicities which included oral mucositis, nausea, vomiting and diarrhea. Measurement of inflammatory cytokines was done by ELISA. RESULTS: All patients (100%) in the control group developed grade 3/4 oral mucositis compared to 8/20 (40%) in both resveratrol-copper group 2 plus group 3 combined (P = 0.039). Reduction in inflammatory cytokines: salivary TNF - α (p = 0.012) and IL-1ß (p = 0.009) in dose level I but not in dose level II was observed. CONCLUSIONS: A combination of resveratrol-copper reduced transplant related toxicities in patients with multiple myeloma receiving high dose melphalan. We conclude that relatively inexpensive nutraceuticals may be useful as adjuncts to chemotherapy to reduce its toxicity. REGISTRATION: The trial was registered under Clinical Trial Registry of India (no.CTRI/2018/02/011905).


Assuntos
Melfalan
20.
Asia Pac J Clin Oncol ; 18(1): 99-108, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33629824

RESUMO

BACKGROUND AND AIM: Molecular mechanism of translocation and outcome in variant chronic myeloid leukaemia (vCML) has been a topic of debate. While several cytogenetic studies suggest a low response to Imatinib Mesylate, others demonstrate a similar disease course in both classical and vCML. Besides, many studies comprehensively also link tyrosine kinase domain (TKD) mutations with aggressive clinical outcome. Thus, we aim to study the molecular mechanism of translocation, identify the third partner chromosomes and comment on the disease course and clinical outcome. METHOD: We cytogenetically characterised 25 vCML cases to determine the third partner chromosome, mechanism of translocation and prognostic outcome. We also compared vCML cases with and without TKD mutation to most appropriately outline the clinical consequence and ascertain the potent cause of unresponsiveness to treatment. RESULTS: Third partner chromosome in variant translocation was defined by conventional and molecular cytogenetics. Although in our study most cases showed inadequate clinical response attributable to TKD mutation rather than variant translocation, we observed an inferior outcome in cases involving chromosome 5 as the third partner. CONCLUSION: Thus, we conclude that characterising and reporting new cases of variant translocations, involving various different chromosomes as third partner (with different breakpoints) by cytogenetics, will lead to a better understanding of the disease. To the best of our knowledge, this kind of delineate study has not been applied to precisely comment on the prospects of cytogenetically characterised vCML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Análise Citogenética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Translocação Genética
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