Dr. Marco Ruella obtained his medical degree with high honors and completed his specialization in clinical hematology at the University of Torino, Italy. He was attending physician at the Hematology and Cell Therapy Division of the Mauriziano Hospital and was an Instructor at the Biotechnology School at the University of Torino. From 2012, he was a Post-doctoral Fellow, and then an Instructor at the University of Pennsylvania in the Center for Cellular immunotherapies (Drs. June and Gill). From 2017 to 2018 he served as Associate Director of Dr. June’s laboratory. In 2018, Dr. Ruella was appointed Assistant Professor of Medicine in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania. Dr. Ruella was awarded the inaugural SITC EMD-Serono Cancer Immunotherapy Clinical Fellowship (2014), the AACR-BMS Oncology Fellowship in Clinical Cancer Research (2015), the ASH Scholar Award (2016), a NIH K99-R00 award (2017), the “Paola Campese” Award Leukemia Research (2017), the Cancer Support Community Award (2018), the 2018 ASH Joanne Levy, MD, Memorial Award for Outstanding Achievement and more recently the Gilead Sciences Research Scholar in Hematology/Oncology and the Gabrielle’s Angel Foundation Award (2020). Dr. Ruella is the author of numerous peer-reviewed publications on targeted immunotherapies for hematological cancers and is an inventor in several patents on CART therapy. Phone: 215-746-4880 Address: 3400 Civic Center Blvd PCAM, SPE 8-112
France Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle... more France Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib). Learning Objectives • Treatment of MCL varies significantly between elderly and young patients • In elderly MCL, the achievement of deep responses should balance the management of co-morbidities and treatment toxicity • New targeted agents, like ibrutinib, could potentially change the treatment paradigm for elderly MCL thanks to their high efficacy associated with manageable toxicity Mantle cell lymphoma (MCL) represents 6% to 8% of non-Hodgkin lymphomas and has an annual incidence of 1 to 2 per 100 000 people in the United States and the European Union. 1 MCL typically presents predominantly in males who have late-stage disease and a median age at diagnosis of 65 to 68 years. 2,3 More recent real-world studies indicate that the median age of patients with MCL may be older than 70 years. 4-6 Therefore, MCL is considered a disease of the elderly, and a significant subset of patients displays reduced performance status at diagnosis. Overall, MCL has a poor prognosis with 4 to 5 years of median survival, 7 and elderly patients (age 65 to 70 years or older) have a worse outcome compared with younger patients, mostly because of increased treatment-related toxicity. This is reflected by the fact that age is one of the 4 key prognostic factors of the Mantle Cell Lymphoma International Prognostic Index. 8 Elderly MCL patients are typically excluded from dose-intensified chemotherapeutic approaches and stem cell transplantation. However, in the absence of contraindications, they usually receive rituximab plus a chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; bendamustine; or other drugs), with possible rituximab maintenance for 2 years after CHOP (the role of rituximab maintenance after bendamustine is still controversial 9). 1,10 Unfortunately , the majority of elderly MCL patients will relapse and then have a very poor prognosis. Managing relapsing or refractory (r/r) MCL is particularly challenging because these individuals often have a reduced performance status and are particularly prone to experience treatment-related adverse events (AEs) as a result of previous che-motherapies and increased age. Furthermore, unexpected complications of AEs may occur because of coexisting geriatric impairments or comorbidities, sometimes with life-threatening consequences. There is no broadly accepted standard treatment for elderly MCL patients relapsing after first-line therapies; if patients are fit, they can receive further chemotherapy. Nevertheless, in the last few years, multiple new drugs have been evaluated in r/r MCL. The Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) 11 was approved in the United States, the European Union, and other countries for the treatment of MCL patients relapsing after 1 prior therapy. 11 In this population, ibrutinib as a single agent led to an overall response rate (ORR) of 67% with 23% complete responses. These results for ibrutinib compare favorably with other new agents such as bor-tezomib, 12 temsirolimus, 13,14 and lenalidomide. 15 However, responses were not maintained long term in the majority of patients, with a 2-year progression-free survival (PFS) of 31% and a median PFS of 13 months. 16,17 In this article, we review the current knowledge about the role of ibrutinib in MCL and discuss its incorporation into the clinical management of elderly patients with MCL, with an understanding of the potential benefits and shortcomings of this agent.
Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approache... more Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells. The anti-CD19/ CD3 bispecific antibody blinatumomab and anti-CD19 chimeric antigen receptor T cells (CART19) have produced deep responses in patients with relapsed and refractory B-cell acute leukemias. However, although the majority of these patients responds to anti-CD19 immunotherapy, a subset of them still relapses. Interestingly, a novel family of leukemia escape mechanisms has been described, all characterized by the apparent loss of CD19 on the surface of leukemic blasts. This extraordinary finding demonstrates the potent selective pressure of CART19/blinatumomab that drives extreme and specific escape strategies by leukemic blasts. Patients with CD19-negative relapsed leukemia have very poor prognosis and novel approaches to treat and ideally prevent antigen-loss are direly needed. In this review we discuss the incidence, mechanisms and therapeutic approaches for CD19-negative leukemia relapses occuring after CD19-directed T cell immunotherapies and present our future perspective.
Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors ... more Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors against cancer. Chimeric antigen receptor (CAR) T cells are the best-in-class example that genetic engineering of T cells can lead to deep and durable responses, as has been shown in several clinical trials for CD19+ B cell malignancies. As a consequence, in the last few years, several academic institutions and commercial partners have started developing anti-CD19 CAR T cell products. Although most of these T cell products are highly effective in vivo, basic differences among them can generate different performance characteristics and thereby impact their long-term clinical outcome. Several strategies are being implemented in order to solve the current open issues of CART19 therapy: (i) increasing efficacy against indolent B cell leukemias and lymphomas, (ii) avoiding or preventing antigen-loss relapses, (iii) reducing and managing toxicity, and (iv) bringing this CART therapy to routine clinical practice. The field of CART therapies is thriving, and exciting new avenues are opening for both scientists and patients.
Oral Communications CD71 expression (10.7%), and an aberratly homogeneous expression of CD71 (7.1... more Oral Communications CD71 expression (10.7%), and an aberratly homogeneous expression of CD71 (7.1%). In cases with a dianogsis of MDS proven by CM the side-scatter signal tended to be lower in granulocytes as compared to non-MDS cases. Overall, in cases rated by CM as proven MDS, possible MDS, and non-MDS at least one dysplastic feature was found by MFC in 92%, 70%, and 19%, respectively. Similarly, in cases with aberrant karyotypes (excluding loss of Y chromosome), a loss of Y chromosome as sole cytogenetic aberration, and a normal karyotype at least one dysplastic feature was found by MFC in 87%, 31%, and 66%, respectively. The presence of dysplastic features by CM as well as the presence of cytogenetic aberrations tended to be associated with a higher number of dysplastic features by MFC. Discussion: These data suggest that the identification of dysplastic features by MFC is feasible although there is a large heterogeneity in aberrantly expressed antigens. Thus, a comprehensive panel of antibodies must be applied to allow the detection of dysplasia. Future studies will define the role of MFC in optimizing the diagnosis of MDS in cooperation with CM and cytogenetics.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 2012
This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP),... more This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP), in which splenectomy was not possible due to the persistence of a low platelet count despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) and platelet transfusion treatment. As an attempt to increase platelet count prior to performing splenectomy, the thrombopoietin receptor agonist, romiplostim, was administered in combination with steroids and IVIG. A single administration of romiplostim was found to be markedly effective, allowing a rapid and notable platelet increase, required for a well tolerated splenectomy. This case confirms the potent activity of romiplostim in ITP, and indicates that patients with recurrent primary ITP who are unresponsive to conventional immunosuppressive therapy may benefit from the addition of a short course of romiplostim.
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA, 2013
Purpose To evaluate granulocyte colony-stimulating factor (G-CSF) efficacy in accelerating bone r... more Purpose To evaluate granulocyte colony-stimulating factor (G-CSF) efficacy in accelerating bone regeneration following opening-wedge high tibial valgus osteotomy for genu varum. Methods A phase II trial was conducted for evaluating the preoperative administration of G-CSF given at 10 μg/kg/day for 3 consecutive days with an additional half-dose 4 h before the opening-wedge high tibial valgus osteotomy. Overall, 12 patients (Group A) received G-CSF treatment, and the subsequent 12 patients (Group B) underwent surgery without G-CSF. The osteotomy gap was filled by a bone graft substitute. Bone marrow cell (BMC) mobilization was monitored by CD34+ve cell and clonogenic progenitor cell analysis. All patients underwent a clinical (Lysholm Knee Scale and SF-36) and radiographic evaluation preoperatively, as well as at given intervals postsurgery. Results All patients completed the treatment program without major side effects; G-CSF was well tolerated. BMC mobilization occurred in all Group A patients, with median peak values of circulating CD34+ve cells of 110/μL (range 29–256). Circulating clonogenic progenitors paralleled CD34+ve cell levels. A significant improvement in Lysholm Knee Scale was recorded at follow-up in Group A compared to Group B. At the radiographic evaluation, there was a significant increase in osseointegration at the bone-graft junction in Group A at 1, 2, 3 and 6 months postsurgery compared to Group B. The computerized tomography scan of the grafted area at 2 months postsurgery showed no significant difference in the quality of the newly formed bone between the two Groups. Conclusions Although the limited number of patients does not allow firm conclusions, the study suggests that G-CSF can be safely administered preoperatively in subjects undergoing opening-wedge high tibial valgus osteotomy; in addition, the clinical, radiographic and CT monitoring indicate that G-CSF and/or mobilized BMCs may hasten bone graft substitute osseointegration. Level of evidence I.
The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, ... more The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, the epidemiology indicates the increased risk of non-Hodgkin's lymphoma (NHL) development in many AD, and especially in Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. In these AD, the relative risk of NHL occurrence varies between 2 and 4 up to 40 fold higher than in the general population, according to various surveys. Factors favouring or predicting NHL have been reported in detail. B-cell activation and proliferation are part of AD and are essential factors for the onset of malignant cell clones in a deregulated immunological environment. Targeting deregulated or malignant B-cells is the goal of some newly developed treatments. The prototype is anti-CD20 rituximab that has substantially modified the prognosis of B-cell NHL and is also an effective new treatment opportunity for some AD. Similarly, intensified treatments with autologous haematopoietic stem cell transplant (ASCT) that were developed for high-risk lymphoma are now under advanced investigation for use in some refractory AD. Thus, the successful use of rituximab and ASCT in both AD and NHL further emphasizes the close link between these two entities. This review provides details on the main epidemiological features regarding NHL incidence in AD, the pathogenetic factors that favour lymphoma onset and some recent advances in therapeutic approaches that are effective in both autoimmune and malignant lymphoproliferative disorders.
Bone marrow-derived cells (BMCs) include stem cells capable of self-renewal and differentiation i... more Bone marrow-derived cells (BMCs) include stem cells capable of self-renewal and differentiation into a variety of cell types. Administration of granulocyte colony-stimulating factor (G-CSF) induces the circulation of BMCs in the peripheral blood. A phase II prospective trial was carried out for evaluation of BMC mobilization induced by multiple courses of G-CSF in cirrhotic patients. Fifteen patients with advanced liver cirrhosis (Child-Pugh score ≥6 points) were enrolled and treated with a 3-day G-CSF course, administered at 3-month intervals for a total of four courses. BMC mobilization was assessed by evaluating CD34+ve cells using flow cytometry. Expressions of multiple hepatic and stem markers were assessed on mobilized CD34+ve cells. Feasibility and safety were explored; clinical and adverse events were compared to those of a control group. Telomere length was monitored to rule out early cell aging caused by G-CSF. A significant increase in G-CSF-induced circulating CD34+ve cells was consistently observed, although a progressive reduction of peak values was documented from cycle I to IV (p < 0.005). Mobilized CD34+ve cells expressed both stem and multiple hepatocyte markers, including mRNA of albumin and CYP2B6 (cytochrome P2 B6). Treatment was well tolerated, with no severe adverse events and no significant telomere length shortening following G-CSF. The procedure was safe. Overall, ten patients had either improved or had stable liver function tests (such as the Child-Pugh score), whereas five worsened and died from liver-related causes. This study demonstrates that G-CSF can be safely administrated up to four times over a 1-year period in decompensated cirrhotic patients. The repeated BMC mobilization favors the circulation of stem cells coexpressing hepatic markers and mRNA of liver-related genes.
The purpose of this study was to investigate telomere length (TL) in Ph-negative chronic myelopro... more The purpose of this study was to investigate telomere length (TL) in Ph-negative chronic myeloproliferative neoplasms (Ph-neg-CMNs), and the possible association of TL with disease progression and hydroxycarbamide (HU) treatment. TL was analyzed in peripheral blood samples from 239 patients with Ph-neg-CMNs, including polycythemia vera (PV), essential thrombocythemia and myelofibrosis (MF), and compared with age-matched healthy control subjects (CTR), along with some cases of secondary erythrocytosis (SE). More than half of the patients with CMN received at least 1 year of cytoreduction, mainly HU, before TL analysis. JAK2 mutation analysis was performed as well. TL was significantly shortened in patients with CMN compared with CTR (p < 0.0001). PV and MF showed the most pronounced decrease (p < 0.0001), whereas both essential thrombocythemia and SE showed no significant difference in TL compared with CTR. A short TL correlated with JAK2-V617F allele burden greater than 50% (p = 0.0025), age (p = 0.0132) and diagnosis of PV (p = 0.0122). No correlation was found with disease duration, history of thrombosis, cytoreductive treatment, antiaggregation agents, adverse cytogenetics, phlebotomies, or time to evolution to MF. In summary, TL is distinctly shortened in PV and MF, and it inversely correlates with JAK2V617F allele burden. In addition, HU is unlikely to contribute to telomere erosion. Lastly, PV and SE significantly differ in TL. Therefore, TL could be an additional diagnostic marker to identify and monitor Ph-neg-CMN patients.
7110; P ¼ 0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P ¼... more 7110; P ¼ 0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P ¼ NS). We conclude that grafted cells have a major role in determining TL after HSCT.
Resumo: O uso de quimioterapia em altas doses seguido do transplante autólogi de células-tronco h... more Resumo: O uso de quimioterapia em altas doses seguido do transplante autólogi de células-tronco hematopoéticas (TACTH) têm sido largamente empregado e é uma modalidade de tratamento eficaz na maioria dos tumores quimiossensíveis, particularmente os linfomas ...
This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP),... more This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP), in which splenectomy was not possible due to the persistence of a low platelet count despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) and platelet transfusion treatment. As an attempt to increase platelet count prior to performing splenectomy, the thrombopoietin receptor agonist, romiplostim, was administered in combination with steroids and IVIG. A single administration of romiplostim was found to be markedly effective, allowing a rapid and notable platelet increase, required for a well tolerated splenectomy. This case confirms the potent activity of romiplostim in ITP, and indicates that patients with recurrent primary ITP who are unresponsive to conventional immunosuppressive therapy may benefit from the addition of a short course of romiplostim.
Stem cells, namely easily accessible bone marrow-derived cells (BMC), are reportedly capable of t... more Stem cells, namely easily accessible bone marrow-derived cells (BMC), are reportedly capable of tissue repair in different damaged organs and might favor wound healing. The present study was undertaken to evaluate the feasibility and safety of BMC mobilization induced by granulocyte-colony-stimulating factor (G-CSF) in patients undergoing surgery for sacrococcygeal pilonidal cysts (SPC). To evaluate the possible clinical benefit of G-CSF in reducing the time to complete resolution, a comparison with a control group receiving surgery without G-CSF was performed. Eight patients with complex SPC were included in this prospective trial. Patients were treated with G-CSF (5 µg/kg b.i.d.) for 3 consecutive days; standard surgical exeresis of the pilonidal cyst was scheduled on day 2 of mobilization. Mobilization was assessed in terms of circulating CD34(+) cells and granulocyte-macrophage colony-forming unit (CFU-GM) progenitors. Mobilization of CD34(+) cells and CFU-GM occurred in all patients, along with a marked increase in white blood cells (median peak value 28 435/µL, day 3). G-CSF was well tolerated and no adverse events occurred. All patients received the planned surgical treatment without any complications. Interestingly, the G-CSF group patients had a median time to resolution (117 days, range 110-130) significantly shorter than control patients (145 days, range 118-168) (P = 0.034). G-CSF administration, along with BMC mobilization, is feasible and well tolerated in patients undergoing surgery for SPC; clinical results compare favorably with those observed in controls not receiving G-CSF; the results suggest the potential use of G-CSF as an additional treatment to accelerate wound healing in patients undergoing surgery.
The outcome of lymphoma has definitely improved over the last few decades which is mainly due to ... more The outcome of lymphoma has definitely improved over the last few decades which is mainly due to the introduction and development of novel and effective therapeutic approaches. Nevertheless, a small though notable group of patients may display a poor response to treatments, with a true refractoriness or a transient response followed by early relapse. The present review addresses the issue of refractory disease among patients with lymphoma, focusing on the overall incidence and the main clinical aspects associated with refractoriness.
BACKGROUND: Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter o... more BACKGROUND: Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 ( 90 Y)-ibritumomab tiuxetan. METHODS: The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non-Hodgkin lymphoma (NHL) who underwent an autograft after high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with 90 Y-ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated. RESULTS: At a median follow-up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD-RIT, and the 5-year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte-macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched-pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy-based myeloablative conditioning demonstrated a 8.05% 5-year cumulative incidence of sMDS/AML. CONCLUSIONS: HD-RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non-negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy-based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD-RIT. Cancer 2011;117:5074-84. V C 2011 American Cancer Society.
Various agents, including chemotherapeutic drugs, can induce cell senescence. However, the mechan... more Various agents, including chemotherapeutic drugs, can induce cell senescence. However, the mechanisms involved in the aging pathway, particularly the stress that chemotherapy imposes on telomeres, are still undefined. To address these issues, human mesenchymal stem cells (MSCs) were assessed as target cells to investigate the initiation of the aging process by chemotherapy. The MSCs were obtained from bone marrow (BM) cells from normal adults and grown in the presence of platelet lysates. Cultured MSCs were identified for immunophenotype, and for growth and differentiation properties. The MSCs were exposed to 10 nM doxorubicin and 500 ng/mL etoposide, sublethal doses that induce DNA double-stranded breaks. Telomere length (TL) was assessed by flow-fluorescence in situ hybridization and Southern blotting. Initial TL shortening was detectable in MSCs at 5 days after drug exposure, with progressive reduction compared with untreated cells at 7, 14, 21, and 28 days in culture. After a single exposure, MSCs were unable to regain the lost telomere sequences for up to 28 days in culture. The ATM phosphorylation was documented early after drug exposure, while no telomerase activation was observed. Chemotherapy-induced TL shortening was associated with reduced clonogenic activity in vitro and accelerated adipose differentiation. Analogous behavior in the differentiation pattern was observed in naturally aged MSCs. These results indicate that cultured MSCs represent a useful cellular model to investigate novel drugs that may favor or, conversely, might prevent TL loss in human stem cells. The TL shortening is a permanent signature of previous chemotherapy-mediated DNA damage, and predicts impaired proliferative and differentiation potential. Ó
France Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle... more France Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib). Learning Objectives • Treatment of MCL varies significantly between elderly and young patients • In elderly MCL, the achievement of deep responses should balance the management of co-morbidities and treatment toxicity • New targeted agents, like ibrutinib, could potentially change the treatment paradigm for elderly MCL thanks to their high efficacy associated with manageable toxicity Mantle cell lymphoma (MCL) represents 6% to 8% of non-Hodgkin lymphomas and has an annual incidence of 1 to 2 per 100 000 people in the United States and the European Union. 1 MCL typically presents predominantly in males who have late-stage disease and a median age at diagnosis of 65 to 68 years. 2,3 More recent real-world studies indicate that the median age of patients with MCL may be older than 70 years. 4-6 Therefore, MCL is considered a disease of the elderly, and a significant subset of patients displays reduced performance status at diagnosis. Overall, MCL has a poor prognosis with 4 to 5 years of median survival, 7 and elderly patients (age 65 to 70 years or older) have a worse outcome compared with younger patients, mostly because of increased treatment-related toxicity. This is reflected by the fact that age is one of the 4 key prognostic factors of the Mantle Cell Lymphoma International Prognostic Index. 8 Elderly MCL patients are typically excluded from dose-intensified chemotherapeutic approaches and stem cell transplantation. However, in the absence of contraindications, they usually receive rituximab plus a chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; bendamustine; or other drugs), with possible rituximab maintenance for 2 years after CHOP (the role of rituximab maintenance after bendamustine is still controversial 9). 1,10 Unfortunately , the majority of elderly MCL patients will relapse and then have a very poor prognosis. Managing relapsing or refractory (r/r) MCL is particularly challenging because these individuals often have a reduced performance status and are particularly prone to experience treatment-related adverse events (AEs) as a result of previous che-motherapies and increased age. Furthermore, unexpected complications of AEs may occur because of coexisting geriatric impairments or comorbidities, sometimes with life-threatening consequences. There is no broadly accepted standard treatment for elderly MCL patients relapsing after first-line therapies; if patients are fit, they can receive further chemotherapy. Nevertheless, in the last few years, multiple new drugs have been evaluated in r/r MCL. The Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) 11 was approved in the United States, the European Union, and other countries for the treatment of MCL patients relapsing after 1 prior therapy. 11 In this population, ibrutinib as a single agent led to an overall response rate (ORR) of 67% with 23% complete responses. These results for ibrutinib compare favorably with other new agents such as bor-tezomib, 12 temsirolimus, 13,14 and lenalidomide. 15 However, responses were not maintained long term in the majority of patients, with a 2-year progression-free survival (PFS) of 31% and a median PFS of 13 months. 16,17 In this article, we review the current knowledge about the role of ibrutinib in MCL and discuss its incorporation into the clinical management of elderly patients with MCL, with an understanding of the potential benefits and shortcomings of this agent.
Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approache... more Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells. The anti-CD19/ CD3 bispecific antibody blinatumomab and anti-CD19 chimeric antigen receptor T cells (CART19) have produced deep responses in patients with relapsed and refractory B-cell acute leukemias. However, although the majority of these patients responds to anti-CD19 immunotherapy, a subset of them still relapses. Interestingly, a novel family of leukemia escape mechanisms has been described, all characterized by the apparent loss of CD19 on the surface of leukemic blasts. This extraordinary finding demonstrates the potent selective pressure of CART19/blinatumomab that drives extreme and specific escape strategies by leukemic blasts. Patients with CD19-negative relapsed leukemia have very poor prognosis and novel approaches to treat and ideally prevent antigen-loss are direly needed. In this review we discuss the incidence, mechanisms and therapeutic approaches for CD19-negative leukemia relapses occuring after CD19-directed T cell immunotherapies and present our future perspective.
Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors ... more Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors against cancer. Chimeric antigen receptor (CAR) T cells are the best-in-class example that genetic engineering of T cells can lead to deep and durable responses, as has been shown in several clinical trials for CD19+ B cell malignancies. As a consequence, in the last few years, several academic institutions and commercial partners have started developing anti-CD19 CAR T cell products. Although most of these T cell products are highly effective in vivo, basic differences among them can generate different performance characteristics and thereby impact their long-term clinical outcome. Several strategies are being implemented in order to solve the current open issues of CART19 therapy: (i) increasing efficacy against indolent B cell leukemias and lymphomas, (ii) avoiding or preventing antigen-loss relapses, (iii) reducing and managing toxicity, and (iv) bringing this CART therapy to routine clinical practice. The field of CART therapies is thriving, and exciting new avenues are opening for both scientists and patients.
Oral Communications CD71 expression (10.7%), and an aberratly homogeneous expression of CD71 (7.1... more Oral Communications CD71 expression (10.7%), and an aberratly homogeneous expression of CD71 (7.1%). In cases with a dianogsis of MDS proven by CM the side-scatter signal tended to be lower in granulocytes as compared to non-MDS cases. Overall, in cases rated by CM as proven MDS, possible MDS, and non-MDS at least one dysplastic feature was found by MFC in 92%, 70%, and 19%, respectively. Similarly, in cases with aberrant karyotypes (excluding loss of Y chromosome), a loss of Y chromosome as sole cytogenetic aberration, and a normal karyotype at least one dysplastic feature was found by MFC in 87%, 31%, and 66%, respectively. The presence of dysplastic features by CM as well as the presence of cytogenetic aberrations tended to be associated with a higher number of dysplastic features by MFC. Discussion: These data suggest that the identification of dysplastic features by MFC is feasible although there is a large heterogeneity in aberrantly expressed antigens. Thus, a comprehensive panel of antibodies must be applied to allow the detection of dysplasia. Future studies will define the role of MFC in optimizing the diagnosis of MDS in cooperation with CM and cytogenetics.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 2012
This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP),... more This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP), in which splenectomy was not possible due to the persistence of a low platelet count despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) and platelet transfusion treatment. As an attempt to increase platelet count prior to performing splenectomy, the thrombopoietin receptor agonist, romiplostim, was administered in combination with steroids and IVIG. A single administration of romiplostim was found to be markedly effective, allowing a rapid and notable platelet increase, required for a well tolerated splenectomy. This case confirms the potent activity of romiplostim in ITP, and indicates that patients with recurrent primary ITP who are unresponsive to conventional immunosuppressive therapy may benefit from the addition of a short course of romiplostim.
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA, 2013
Purpose To evaluate granulocyte colony-stimulating factor (G-CSF) efficacy in accelerating bone r... more Purpose To evaluate granulocyte colony-stimulating factor (G-CSF) efficacy in accelerating bone regeneration following opening-wedge high tibial valgus osteotomy for genu varum. Methods A phase II trial was conducted for evaluating the preoperative administration of G-CSF given at 10 μg/kg/day for 3 consecutive days with an additional half-dose 4 h before the opening-wedge high tibial valgus osteotomy. Overall, 12 patients (Group A) received G-CSF treatment, and the subsequent 12 patients (Group B) underwent surgery without G-CSF. The osteotomy gap was filled by a bone graft substitute. Bone marrow cell (BMC) mobilization was monitored by CD34+ve cell and clonogenic progenitor cell analysis. All patients underwent a clinical (Lysholm Knee Scale and SF-36) and radiographic evaluation preoperatively, as well as at given intervals postsurgery. Results All patients completed the treatment program without major side effects; G-CSF was well tolerated. BMC mobilization occurred in all Group A patients, with median peak values of circulating CD34+ve cells of 110/μL (range 29–256). Circulating clonogenic progenitors paralleled CD34+ve cell levels. A significant improvement in Lysholm Knee Scale was recorded at follow-up in Group A compared to Group B. At the radiographic evaluation, there was a significant increase in osseointegration at the bone-graft junction in Group A at 1, 2, 3 and 6 months postsurgery compared to Group B. The computerized tomography scan of the grafted area at 2 months postsurgery showed no significant difference in the quality of the newly formed bone between the two Groups. Conclusions Although the limited number of patients does not allow firm conclusions, the study suggests that G-CSF can be safely administered preoperatively in subjects undergoing opening-wedge high tibial valgus osteotomy; in addition, the clinical, radiographic and CT monitoring indicate that G-CSF and/or mobilized BMCs may hasten bone graft substitute osseointegration. Level of evidence I.
The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, ... more The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, the epidemiology indicates the increased risk of non-Hodgkin's lymphoma (NHL) development in many AD, and especially in Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. In these AD, the relative risk of NHL occurrence varies between 2 and 4 up to 40 fold higher than in the general population, according to various surveys. Factors favouring or predicting NHL have been reported in detail. B-cell activation and proliferation are part of AD and are essential factors for the onset of malignant cell clones in a deregulated immunological environment. Targeting deregulated or malignant B-cells is the goal of some newly developed treatments. The prototype is anti-CD20 rituximab that has substantially modified the prognosis of B-cell NHL and is also an effective new treatment opportunity for some AD. Similarly, intensified treatments with autologous haematopoietic stem cell transplant (ASCT) that were developed for high-risk lymphoma are now under advanced investigation for use in some refractory AD. Thus, the successful use of rituximab and ASCT in both AD and NHL further emphasizes the close link between these two entities. This review provides details on the main epidemiological features regarding NHL incidence in AD, the pathogenetic factors that favour lymphoma onset and some recent advances in therapeutic approaches that are effective in both autoimmune and malignant lymphoproliferative disorders.
Bone marrow-derived cells (BMCs) include stem cells capable of self-renewal and differentiation i... more Bone marrow-derived cells (BMCs) include stem cells capable of self-renewal and differentiation into a variety of cell types. Administration of granulocyte colony-stimulating factor (G-CSF) induces the circulation of BMCs in the peripheral blood. A phase II prospective trial was carried out for evaluation of BMC mobilization induced by multiple courses of G-CSF in cirrhotic patients. Fifteen patients with advanced liver cirrhosis (Child-Pugh score ≥6 points) were enrolled and treated with a 3-day G-CSF course, administered at 3-month intervals for a total of four courses. BMC mobilization was assessed by evaluating CD34+ve cells using flow cytometry. Expressions of multiple hepatic and stem markers were assessed on mobilized CD34+ve cells. Feasibility and safety were explored; clinical and adverse events were compared to those of a control group. Telomere length was monitored to rule out early cell aging caused by G-CSF. A significant increase in G-CSF-induced circulating CD34+ve cells was consistently observed, although a progressive reduction of peak values was documented from cycle I to IV (p < 0.005). Mobilized CD34+ve cells expressed both stem and multiple hepatocyte markers, including mRNA of albumin and CYP2B6 (cytochrome P2 B6). Treatment was well tolerated, with no severe adverse events and no significant telomere length shortening following G-CSF. The procedure was safe. Overall, ten patients had either improved or had stable liver function tests (such as the Child-Pugh score), whereas five worsened and died from liver-related causes. This study demonstrates that G-CSF can be safely administrated up to four times over a 1-year period in decompensated cirrhotic patients. The repeated BMC mobilization favors the circulation of stem cells coexpressing hepatic markers and mRNA of liver-related genes.
The purpose of this study was to investigate telomere length (TL) in Ph-negative chronic myelopro... more The purpose of this study was to investigate telomere length (TL) in Ph-negative chronic myeloproliferative neoplasms (Ph-neg-CMNs), and the possible association of TL with disease progression and hydroxycarbamide (HU) treatment. TL was analyzed in peripheral blood samples from 239 patients with Ph-neg-CMNs, including polycythemia vera (PV), essential thrombocythemia and myelofibrosis (MF), and compared with age-matched healthy control subjects (CTR), along with some cases of secondary erythrocytosis (SE). More than half of the patients with CMN received at least 1 year of cytoreduction, mainly HU, before TL analysis. JAK2 mutation analysis was performed as well. TL was significantly shortened in patients with CMN compared with CTR (p < 0.0001). PV and MF showed the most pronounced decrease (p < 0.0001), whereas both essential thrombocythemia and SE showed no significant difference in TL compared with CTR. A short TL correlated with JAK2-V617F allele burden greater than 50% (p = 0.0025), age (p = 0.0132) and diagnosis of PV (p = 0.0122). No correlation was found with disease duration, history of thrombosis, cytoreductive treatment, antiaggregation agents, adverse cytogenetics, phlebotomies, or time to evolution to MF. In summary, TL is distinctly shortened in PV and MF, and it inversely correlates with JAK2V617F allele burden. In addition, HU is unlikely to contribute to telomere erosion. Lastly, PV and SE significantly differ in TL. Therefore, TL could be an additional diagnostic marker to identify and monitor Ph-neg-CMN patients.
7110; P ¼ 0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P ¼... more 7110; P ¼ 0.0005); following HSCT, BM TL (median 7380 bp) was identical to that of the graft (P ¼ NS). We conclude that grafted cells have a major role in determining TL after HSCT.
Resumo: O uso de quimioterapia em altas doses seguido do transplante autólogi de células-tronco h... more Resumo: O uso de quimioterapia em altas doses seguido do transplante autólogi de células-tronco hematopoéticas (TACTH) têm sido largamente empregado e é uma modalidade de tratamento eficaz na maioria dos tumores quimiossensíveis, particularmente os linfomas ...
This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP),... more This case report describes a patient with relapsed primary immune thrombocytopenic purpura (ITP), in which splenectomy was not possible due to the persistence of a low platelet count despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) and platelet transfusion treatment. As an attempt to increase platelet count prior to performing splenectomy, the thrombopoietin receptor agonist, romiplostim, was administered in combination with steroids and IVIG. A single administration of romiplostim was found to be markedly effective, allowing a rapid and notable platelet increase, required for a well tolerated splenectomy. This case confirms the potent activity of romiplostim in ITP, and indicates that patients with recurrent primary ITP who are unresponsive to conventional immunosuppressive therapy may benefit from the addition of a short course of romiplostim.
Stem cells, namely easily accessible bone marrow-derived cells (BMC), are reportedly capable of t... more Stem cells, namely easily accessible bone marrow-derived cells (BMC), are reportedly capable of tissue repair in different damaged organs and might favor wound healing. The present study was undertaken to evaluate the feasibility and safety of BMC mobilization induced by granulocyte-colony-stimulating factor (G-CSF) in patients undergoing surgery for sacrococcygeal pilonidal cysts (SPC). To evaluate the possible clinical benefit of G-CSF in reducing the time to complete resolution, a comparison with a control group receiving surgery without G-CSF was performed. Eight patients with complex SPC were included in this prospective trial. Patients were treated with G-CSF (5 µg/kg b.i.d.) for 3 consecutive days; standard surgical exeresis of the pilonidal cyst was scheduled on day 2 of mobilization. Mobilization was assessed in terms of circulating CD34(+) cells and granulocyte-macrophage colony-forming unit (CFU-GM) progenitors. Mobilization of CD34(+) cells and CFU-GM occurred in all patients, along with a marked increase in white blood cells (median peak value 28 435/µL, day 3). G-CSF was well tolerated and no adverse events occurred. All patients received the planned surgical treatment without any complications. Interestingly, the G-CSF group patients had a median time to resolution (117 days, range 110-130) significantly shorter than control patients (145 days, range 118-168) (P = 0.034). G-CSF administration, along with BMC mobilization, is feasible and well tolerated in patients undergoing surgery for SPC; clinical results compare favorably with those observed in controls not receiving G-CSF; the results suggest the potential use of G-CSF as an additional treatment to accelerate wound healing in patients undergoing surgery.
The outcome of lymphoma has definitely improved over the last few decades which is mainly due to ... more The outcome of lymphoma has definitely improved over the last few decades which is mainly due to the introduction and development of novel and effective therapeutic approaches. Nevertheless, a small though notable group of patients may display a poor response to treatments, with a true refractoriness or a transient response followed by early relapse. The present review addresses the issue of refractory disease among patients with lymphoma, focusing on the overall incidence and the main clinical aspects associated with refractoriness.
BACKGROUND: Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter o... more BACKGROUND: Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 ( 90 Y)-ibritumomab tiuxetan. METHODS: The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non-Hodgkin lymphoma (NHL) who underwent an autograft after high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with 90 Y-ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated. RESULTS: At a median follow-up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD-RIT, and the 5-year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte-macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched-pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy-based myeloablative conditioning demonstrated a 8.05% 5-year cumulative incidence of sMDS/AML. CONCLUSIONS: HD-RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non-negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy-based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD-RIT. Cancer 2011;117:5074-84. V C 2011 American Cancer Society.
Various agents, including chemotherapeutic drugs, can induce cell senescence. However, the mechan... more Various agents, including chemotherapeutic drugs, can induce cell senescence. However, the mechanisms involved in the aging pathway, particularly the stress that chemotherapy imposes on telomeres, are still undefined. To address these issues, human mesenchymal stem cells (MSCs) were assessed as target cells to investigate the initiation of the aging process by chemotherapy. The MSCs were obtained from bone marrow (BM) cells from normal adults and grown in the presence of platelet lysates. Cultured MSCs were identified for immunophenotype, and for growth and differentiation properties. The MSCs were exposed to 10 nM doxorubicin and 500 ng/mL etoposide, sublethal doses that induce DNA double-stranded breaks. Telomere length (TL) was assessed by flow-fluorescence in situ hybridization and Southern blotting. Initial TL shortening was detectable in MSCs at 5 days after drug exposure, with progressive reduction compared with untreated cells at 7, 14, 21, and 28 days in culture. After a single exposure, MSCs were unable to regain the lost telomere sequences for up to 28 days in culture. The ATM phosphorylation was documented early after drug exposure, while no telomerase activation was observed. Chemotherapy-induced TL shortening was associated with reduced clonogenic activity in vitro and accelerated adipose differentiation. Analogous behavior in the differentiation pattern was observed in naturally aged MSCs. These results indicate that cultured MSCs represent a useful cellular model to investigate novel drugs that may favor or, conversely, might prevent TL loss in human stem cells. The TL shortening is a permanent signature of previous chemotherapy-mediated DNA damage, and predicts impaired proliferative and differentiation potential. Ó
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