Skeletal erosion has been found to represent an independent prognostic indicator in patients with... more Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression. Bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and was correlated with both local expansion of metabolically active bone marrow documented by FDG uptake and with the number of RANKL + cells present in the circulating blood. In immune-deficient NOD/Shi-scid, γcnull (NSG) mice, administration of CLL cells caus...
Early-interim fluorodeoxyglucose (FDG)-PET scan after two ABVD (doxorubicin, bleomycin, vinblasti... more Early-interim fluorodeoxyglucose (FDG)-PET scan after two ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy courses (PET-2) represents the most effective predictor of treatment outcome in classical Hodgkin's lymphoma. We aimed to assess the predictive value of PET-2 combined with tissue biomarkers in neoplastic and microenvironmental cells for this disease. We enrolled 208 patients with classical Hodgkin's lymphoma and treated with ABVD (training set), from Jan 1, 2002, to Dec 31, 2009, and validated the results in a fully matched independent cohort of 102 patients with classical Hodgkin's lymphoma (validation set), enrolled from Jan 1, 2008, to Dec 31, 2012. The inclusion criteria for both the training and validation sets were: the availability of a representative formalin-fixed, paraffin-embedded tissue sample collected at diagnosis; treatment with ABVD with or without radiotherapy; baseline staging and interim restaging after two ABVD courses with FDG-PET; no treatment change based solely on interim PET result; and HIV-negative status. We used Cox multivariate analysis classification and regression tree (CART) to compare the predictive values of these markers with that of PET-2 and to assess the biomarkers' ability to correctly classify patients whose outcome was incorrectly predicted by PET-2. In multivariate analysis, PET-2 was the only factor able to predict both progression-free survival (hazard ratio [HR] 33·3 [95% CI 13·6-83·3]; p<0·0001) and overall survival (HR 31·3 [95% CI 3·7-58·9]; p=0·002). In the training set, no factor had a stronger adverse predictive value than a positive PET-2 scan and none was able to correctly reclassify PET-2 positive patients. In PET-2 negative patients, expression of CD68 (≥25%) and PD1 (diffuse or rosetting pattern) in microenvironmental cells, and STAT1 negativity in Hodgkin Reed Sternberg cells identified a subset of PET-2 negative patients with a 3 year progression-free survival significantly lower than that of the remaining PET-2 negative population (21 [64%] of 33 [95% CI 45·2-79·0] vs 130 [95%] of 137 [95% CI 89·4-97·7]; p<0·0001). These findings were reproduced in the validation set. The CART algorithm correctly predicted the response to treatment in more than a half of patients who had a relapse or disease progression despite a negative PET-2 scan, thus increasing the negative predictive value of PET-2. In keeping with preliminary results from interim PET response adapted clinical trials of patients with advanced Hodgkin's lymphoma, there might be a non-negligible proportion of treatment failures in the interim PET negative group treated with standard ABVD. Italian Association for Cancer Research, Bologna Association against leukaemia, lymphoma and myeloma, and Bologna University.
ABSTRACT Hodgkin lymphoma (HL) is a highly curable disease, as most HL patients become long-term ... more ABSTRACT Hodgkin lymphoma (HL) is a highly curable disease, as most HL patients become long-term survivors, with 10-years cure and survival rates after first-line treatment exceeding 80 and 90 %, respectively. Despite these rewarding results, 10-15 % of early stage and 20-25 % of advanced stage patients became chemo-refractory to first-line treatment, and nearly half of them ultimately succumb to their disease. On the other hand, a small but significant fraction of long-term survivors, especially those treated with combined chemoradiation, experience treatment related morbidity and mortality with cardiovascular events and secondary neoplasms arising 5-20 years after the end of therapy. Therefore, an unfulfilled need still exists for a risk-adapted strategy, with a very effective treatment in high-risk patients and a low toxicity regimen in the vast majority of patients who are indeed chemo sensitive. Interim PET scan, performed after few cycles of chemotherapy proved the main predictor of treatment outcome in ABVD-treated patients and superseded the predictive role of traditional prognostic markers. Moreover, simple and reproducible rules for interim PET interpretation agreed among experts have been validated in HL, and are now available for the clinical practice. A number of phase II trials yielded the prof of concept that adapting treatment to interim PET result could ultimately increase long-term disease control in the entire patient population, compared to that obtained with the standard chemotherapy approach. In the present article the results of these pioneer single-centre small trials, as well as the preliminary results of large international prospective trials will be reviewed.
International Journal of Hematologic Oncology, 2013
ABSTRACT Despite a marked improvement in lymphoma treatment outcome, current prognostic models, r... more ABSTRACT Despite a marked improvement in lymphoma treatment outcome, current prognostic models, relying on a pretreatment set of static clinical variables, appear unable to support a risk-adapted therapeutic strategy. On the other hand, functional imaging with 18F-fluoro-2-deoxy-D-glucose (FDG)-PET proved to be a reliable tool to dynamically assess tumor FDG uptake changes during and after treatment. In this article we aim to review the prognostic value of FDG-PET in all the stages of Hodgkin’s and non-Hodgkin’s lymphoma management, without the intent to address the diagnostic value of PET or to replace available consensus guidelines. In particular we focused on two critical issues: the cost–effectiveness of PET in the overall strategy of lymphoma diagnosis and treatment; and ongoing clinical trials adopting an interim PET-based strategy to modulate treatment intensity based on PET results. Finally, new trends in multimodality imaging, as well as in new radiopharmaceutical tracers, are briefly reviewed.
(18) F-2-deoxy-d-glucose positron emission tomography (FDG-PET), combined with a multidetector he... more (18) F-2-deoxy-d-glucose positron emission tomography (FDG-PET), combined with a multidetector helical CT (PET/CT) has emerged, in the past decade as one of the most important prognostic tool for lymphoma management. Besides proving as the only imaging technique able to recapitulate all the information yielded by the standard radiological staging and restaging, it provided new essential information for chemosensitivity assessment and radiotherapy planning. In lymphoma staging, functional imaging (FI) by PET/CT was shown to be more accurate than conventional radiological (anatomical) imaging to detect nodal and extranodal involvement, whereas in posttreatment restaging it showed a superior predictive value on treatment outcome. In Hodgkin lymphoma (HL), FI concurred to delineate a new paradigm of therapy in which PET is considered an essential tool to guide physician's choice on treatment intensity and modality. In fact, PET proved very useful for: 1) assessing chemosensitivity early during treatment to predict final therapy outcome; 2) managing a residual mass, detected by CT scan in up to two thirds of patients at the end of chemotherapy; and 3) planning radiotherapy in early-stage disease when conformal radiotherapy fields are used to spare toxicity to adjacent tissues. The early chemosensitivity assessment is the underpinnings of a new therapeutic strategy in HL, aimed at minimizing treatment-related toxicity while maintaining treatment efficacy. Several clinical trials are currently underway to test this hypothesis. In diffuse, large, B-cell lymphoma (DLBCL), PET/CT proved very useful: 1) in lymphoma staging, leading to upward stage migration in one third of the patients; and 2) to identify patients benefiting from consolidation radiotherapy for FDG-avid, single mass or limited-extension disease. Different to HL, the role of interim PET in DLBCL remains controversial. In follicular lymphoma (FL) preliminary studies PET/CT proved useful, in baseline staging to predict time to treatment in patients in which a watchful observation without treatment (watch and wait) was chosen as therapeutic approach treatment. In FL end-of-treatment PET/CT proved the most powerful prognostic tool to predict long-term treatment outcome.
The prognostic models in Hodgkin lymphoma (HL) such as the International Prognostic Score (IPS), ... more The prognostic models in Hodgkin lymphoma (HL) such as the International Prognostic Score (IPS), retrospectively constructed in the last twenty years from different cohorts of patients treated with ABVD or ABVD-equivalent regimens have been shown a limited predictive value on treatment outcome when applied to a prospective cohort of patients. In the turn of millennium a new class of prognostic factors has emerged, aimed to test the chemosensitivity to treatment in a single patient-basis, such as the minimal residual disease (MRD) assessment with molecular biology, or interim PET/CT performed early during treatment. The main challenge in the management of both early and advanced-stage HL is to achieve a durable remission or cure while minimizing therapy toxicity. An adaptive therapy strategy based on interim PET results could distinguish high from low-risk patients: the former with a potential benefit from an intensify regimen, the latter in whom treatment could be de-escalated or abbreviated for minimizing long-term adverse effects. Conversely, chemosensitivity evaluation in early-stage HL has been the underpinning of de-escalation trials aimed at assessing the safety and the efficacy of omitting radiotherapy in interim PET-negative patients. Brentuximab Vedotin (BV) is a novel antibody-drug conjugate targeting CD30 linked to a potent synthetic antitubulin chemotherapeutic agent, monomethyl auristatin E (MME). BV showed an impressive activity against refractory/relapsed HL and now is being incorporated in a modified ABVD schedule in first-line treatment of HL, with promising efficacy and a low toxicity profile. This novel therapeutic strategy will tell us if traditional ABVD or BEACOPP chemotherapy could be abandoned for the brand-new targeted therapy. Despite the brilliant results of HL treatment, which proved able to achieve a long-term disease control in 80-90% of the patients, the search of new prognostic has continued over the last two decades and the progress of the knowledge of the pathobiology of HL has led to a discovery of a series of markers related to microenvironment of HL tissue and molecular mechanisms to escape host immune reaction against the tumor. The strong association between the locus A of the human leukocyte antigen (HLA-A) system and EBV-positive HL suggests that both an abnormal antigen presentation and some specific EBV antigen per se could play a pivotal role in the pathogenesis of cHL. In EBV+HL patients, the susceptibility or the resistance to develop HL depends on the HLA allele A-*01 or A-*02, respectively. Tumor escape mechanism to block the immune response of the host against the neoplastic tissue is one of the property of a recently discovered subset of myeloid-derived suppressor cells (MDSC) that induce tumor vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, MDSC derive from multipotent progenitor cells that can differentiate in the tissue as monocyte-derived MDSC (Mo-MDSC) with a phenotype CD14+/dull and granulocyte-derived MDSC (G-MDSC) expressing CD15 on cell surface. The latter were shown to produce arginase. Recent investigations suggest that MDSC present in the bone marrow in patients with several solid and hematological cancers in response to chemokine release in the tumor site are correlated with tumor-associated macrophages (TAM). Both TAM and MDSC have been strongly associated with a significantly worse prognosis in HL. As a consequence, several efforts are ongoing to standardize the methods to assess TAM and MDSC and prospective studies are being planned to validate their prognostic role.
Skeletal erosion has been found to represent an independent prognostic indicator in patients with... more Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression. Bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and was correlated with both local expansion of metabolically active bone marrow documented by FDG uptake and with the number of RANKL + cells present in the circulating blood. In immune-deficient NOD/Shi-scid, γcnull (NSG) mice, administration of CLL cells caus...
Early-interim fluorodeoxyglucose (FDG)-PET scan after two ABVD (doxorubicin, bleomycin, vinblasti... more Early-interim fluorodeoxyglucose (FDG)-PET scan after two ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy courses (PET-2) represents the most effective predictor of treatment outcome in classical Hodgkin's lymphoma. We aimed to assess the predictive value of PET-2 combined with tissue biomarkers in neoplastic and microenvironmental cells for this disease. We enrolled 208 patients with classical Hodgkin's lymphoma and treated with ABVD (training set), from Jan 1, 2002, to Dec 31, 2009, and validated the results in a fully matched independent cohort of 102 patients with classical Hodgkin's lymphoma (validation set), enrolled from Jan 1, 2008, to Dec 31, 2012. The inclusion criteria for both the training and validation sets were: the availability of a representative formalin-fixed, paraffin-embedded tissue sample collected at diagnosis; treatment with ABVD with or without radiotherapy; baseline staging and interim restaging after two ABVD courses with FDG-PET; no treatment change based solely on interim PET result; and HIV-negative status. We used Cox multivariate analysis classification and regression tree (CART) to compare the predictive values of these markers with that of PET-2 and to assess the biomarkers' ability to correctly classify patients whose outcome was incorrectly predicted by PET-2. In multivariate analysis, PET-2 was the only factor able to predict both progression-free survival (hazard ratio [HR] 33·3 [95% CI 13·6-83·3]; p<0·0001) and overall survival (HR 31·3 [95% CI 3·7-58·9]; p=0·002). In the training set, no factor had a stronger adverse predictive value than a positive PET-2 scan and none was able to correctly reclassify PET-2 positive patients. In PET-2 negative patients, expression of CD68 (≥25%) and PD1 (diffuse or rosetting pattern) in microenvironmental cells, and STAT1 negativity in Hodgkin Reed Sternberg cells identified a subset of PET-2 negative patients with a 3 year progression-free survival significantly lower than that of the remaining PET-2 negative population (21 [64%] of 33 [95% CI 45·2-79·0] vs 130 [95%] of 137 [95% CI 89·4-97·7]; p<0·0001). These findings were reproduced in the validation set. The CART algorithm correctly predicted the response to treatment in more than a half of patients who had a relapse or disease progression despite a negative PET-2 scan, thus increasing the negative predictive value of PET-2. In keeping with preliminary results from interim PET response adapted clinical trials of patients with advanced Hodgkin's lymphoma, there might be a non-negligible proportion of treatment failures in the interim PET negative group treated with standard ABVD. Italian Association for Cancer Research, Bologna Association against leukaemia, lymphoma and myeloma, and Bologna University.
ABSTRACT Hodgkin lymphoma (HL) is a highly curable disease, as most HL patients become long-term ... more ABSTRACT Hodgkin lymphoma (HL) is a highly curable disease, as most HL patients become long-term survivors, with 10-years cure and survival rates after first-line treatment exceeding 80 and 90 %, respectively. Despite these rewarding results, 10-15 % of early stage and 20-25 % of advanced stage patients became chemo-refractory to first-line treatment, and nearly half of them ultimately succumb to their disease. On the other hand, a small but significant fraction of long-term survivors, especially those treated with combined chemoradiation, experience treatment related morbidity and mortality with cardiovascular events and secondary neoplasms arising 5-20 years after the end of therapy. Therefore, an unfulfilled need still exists for a risk-adapted strategy, with a very effective treatment in high-risk patients and a low toxicity regimen in the vast majority of patients who are indeed chemo sensitive. Interim PET scan, performed after few cycles of chemotherapy proved the main predictor of treatment outcome in ABVD-treated patients and superseded the predictive role of traditional prognostic markers. Moreover, simple and reproducible rules for interim PET interpretation agreed among experts have been validated in HL, and are now available for the clinical practice. A number of phase II trials yielded the prof of concept that adapting treatment to interim PET result could ultimately increase long-term disease control in the entire patient population, compared to that obtained with the standard chemotherapy approach. In the present article the results of these pioneer single-centre small trials, as well as the preliminary results of large international prospective trials will be reviewed.
International Journal of Hematologic Oncology, 2013
ABSTRACT Despite a marked improvement in lymphoma treatment outcome, current prognostic models, r... more ABSTRACT Despite a marked improvement in lymphoma treatment outcome, current prognostic models, relying on a pretreatment set of static clinical variables, appear unable to support a risk-adapted therapeutic strategy. On the other hand, functional imaging with 18F-fluoro-2-deoxy-D-glucose (FDG)-PET proved to be a reliable tool to dynamically assess tumor FDG uptake changes during and after treatment. In this article we aim to review the prognostic value of FDG-PET in all the stages of Hodgkin’s and non-Hodgkin’s lymphoma management, without the intent to address the diagnostic value of PET or to replace available consensus guidelines. In particular we focused on two critical issues: the cost–effectiveness of PET in the overall strategy of lymphoma diagnosis and treatment; and ongoing clinical trials adopting an interim PET-based strategy to modulate treatment intensity based on PET results. Finally, new trends in multimodality imaging, as well as in new radiopharmaceutical tracers, are briefly reviewed.
(18) F-2-deoxy-d-glucose positron emission tomography (FDG-PET), combined with a multidetector he... more (18) F-2-deoxy-d-glucose positron emission tomography (FDG-PET), combined with a multidetector helical CT (PET/CT) has emerged, in the past decade as one of the most important prognostic tool for lymphoma management. Besides proving as the only imaging technique able to recapitulate all the information yielded by the standard radiological staging and restaging, it provided new essential information for chemosensitivity assessment and radiotherapy planning. In lymphoma staging, functional imaging (FI) by PET/CT was shown to be more accurate than conventional radiological (anatomical) imaging to detect nodal and extranodal involvement, whereas in posttreatment restaging it showed a superior predictive value on treatment outcome. In Hodgkin lymphoma (HL), FI concurred to delineate a new paradigm of therapy in which PET is considered an essential tool to guide physician's choice on treatment intensity and modality. In fact, PET proved very useful for: 1) assessing chemosensitivity early during treatment to predict final therapy outcome; 2) managing a residual mass, detected by CT scan in up to two thirds of patients at the end of chemotherapy; and 3) planning radiotherapy in early-stage disease when conformal radiotherapy fields are used to spare toxicity to adjacent tissues. The early chemosensitivity assessment is the underpinnings of a new therapeutic strategy in HL, aimed at minimizing treatment-related toxicity while maintaining treatment efficacy. Several clinical trials are currently underway to test this hypothesis. In diffuse, large, B-cell lymphoma (DLBCL), PET/CT proved very useful: 1) in lymphoma staging, leading to upward stage migration in one third of the patients; and 2) to identify patients benefiting from consolidation radiotherapy for FDG-avid, single mass or limited-extension disease. Different to HL, the role of interim PET in DLBCL remains controversial. In follicular lymphoma (FL) preliminary studies PET/CT proved useful, in baseline staging to predict time to treatment in patients in which a watchful observation without treatment (watch and wait) was chosen as therapeutic approach treatment. In FL end-of-treatment PET/CT proved the most powerful prognostic tool to predict long-term treatment outcome.
The prognostic models in Hodgkin lymphoma (HL) such as the International Prognostic Score (IPS), ... more The prognostic models in Hodgkin lymphoma (HL) such as the International Prognostic Score (IPS), retrospectively constructed in the last twenty years from different cohorts of patients treated with ABVD or ABVD-equivalent regimens have been shown a limited predictive value on treatment outcome when applied to a prospective cohort of patients. In the turn of millennium a new class of prognostic factors has emerged, aimed to test the chemosensitivity to treatment in a single patient-basis, such as the minimal residual disease (MRD) assessment with molecular biology, or interim PET/CT performed early during treatment. The main challenge in the management of both early and advanced-stage HL is to achieve a durable remission or cure while minimizing therapy toxicity. An adaptive therapy strategy based on interim PET results could distinguish high from low-risk patients: the former with a potential benefit from an intensify regimen, the latter in whom treatment could be de-escalated or abbreviated for minimizing long-term adverse effects. Conversely, chemosensitivity evaluation in early-stage HL has been the underpinning of de-escalation trials aimed at assessing the safety and the efficacy of omitting radiotherapy in interim PET-negative patients. Brentuximab Vedotin (BV) is a novel antibody-drug conjugate targeting CD30 linked to a potent synthetic antitubulin chemotherapeutic agent, monomethyl auristatin E (MME). BV showed an impressive activity against refractory/relapsed HL and now is being incorporated in a modified ABVD schedule in first-line treatment of HL, with promising efficacy and a low toxicity profile. This novel therapeutic strategy will tell us if traditional ABVD or BEACOPP chemotherapy could be abandoned for the brand-new targeted therapy. Despite the brilliant results of HL treatment, which proved able to achieve a long-term disease control in 80-90% of the patients, the search of new prognostic has continued over the last two decades and the progress of the knowledge of the pathobiology of HL has led to a discovery of a series of markers related to microenvironment of HL tissue and molecular mechanisms to escape host immune reaction against the tumor. The strong association between the locus A of the human leukocyte antigen (HLA-A) system and EBV-positive HL suggests that both an abnormal antigen presentation and some specific EBV antigen per se could play a pivotal role in the pathogenesis of cHL. In EBV+HL patients, the susceptibility or the resistance to develop HL depends on the HLA allele A-*01 or A-*02, respectively. Tumor escape mechanism to block the immune response of the host against the neoplastic tissue is one of the property of a recently discovered subset of myeloid-derived suppressor cells (MDSC) that induce tumor vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, MDSC derive from multipotent progenitor cells that can differentiate in the tissue as monocyte-derived MDSC (Mo-MDSC) with a phenotype CD14+/dull and granulocyte-derived MDSC (G-MDSC) expressing CD15 on cell surface. The latter were shown to produce arginase. Recent investigations suggest that MDSC present in the bone marrow in patients with several solid and hematological cancers in response to chemokine release in the tumor site are correlated with tumor-associated macrophages (TAM). Both TAM and MDSC have been strongly associated with a significantly worse prognosis in HL. As a consequence, several efforts are ongoing to standardize the methods to assess TAM and MDSC and prospective studies are being planned to validate their prognostic role.
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