Publications by authors named "Beatrice Casadei"

44 Publications

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 Mar 3. Epub 2021 Mar 3.

Department of Oncology and Hematology, Humanitas Clinical and Research Center-IRCCS, Rozzano-Milano, Italy.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
March 2021

Erythrodermie mit Brentuximab-Vedotin (Hautnebenwirkungen bei Mycosis fungoides).

J Dtsch Dermatol Ges 2021 01;19(1):99-102

Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1111/ddg.14197_gDOI Listing
January 2021

Treatment and outcomes of primary mediastinal B cell lymphoma: a three-decade monocentric experience with 151 patients.

Ann Hematol 2020 Dec 10. Epub 2020 Dec 10.

IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Primary mediastinal B cell lymphoma is a rare entity and often should be promptly treated as a hematological emergency: The initial treatment decision is crucial for the management of this disease. An observational retrospective study was conducted with the aim to improve information on treatment and outcomes of primary mediastinal B cell lymphoma in real practice. After 12 cycles of MACOP-B regimen (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin , and prednisone) with or without rituximab, 120 patients out of 151 (79.5%) achieved a complete response and 12 (7.9%) a partial response leading to a global response of 87.4%. The 21-year overall survival is 82.6%; progression-free and disease-free survivals are 69.3% and 86.4%, respectively. Regarding the role of radiotherapy (RT), patients with a negative PET scan after MACOP-B did not undergo RT: One out of these 48 (2.1%) showed a relapse at 11 months. All relapsed/refractory patients who achieved a response with checkpoint inhibitors are still in continuous complete response with a median follow-up of 14 months. Data that we have gathered over a 30-year experience in the treatment of primary mediastinal B cell lymphoma patients clearly indicate that a third-generation chemotherapy regimen such as MACOP-B is feasible and easily deliverable on an outpatient basis. Regarding the unmet medical need of relapsed/refractory patients, new encouraging results occurred with the advent of the checkpoint inhibitors.
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http://dx.doi.org/10.1007/s00277-020-04364-0DOI Listing
December 2020

Potential survival benefit for patients receiving autologous hematopoietic stem cell transplantation after checkpoint inhibitors for relapsed/refractory Hodgkin lymphoma: A real-life experience.

Hematol Oncol 2020 Dec 30;38(5):737-741. Epub 2020 Sep 30.

Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia.

In recent years, novel drugs are available for the patients with relapsed/refractory Hodgkin lymphoma (HL), like immune checkpoint inhibitors (CPi). These drugs have been able to rescue a cohort of patients who subsequently could receive an allogeneic stem-cell transplant (SCT). No data were reported for subsequent autologous SCT (ASCT) after CPi. Here, we report our real-life experience in heavily pretreated HL patients undergoing ASCT as consolidation approach after CPi treatment. A retrospective observational study was conducted. Patients had CPi therapy in the context of clinical trials (n = 6) or in the named patient program (n = 7) between July 2014 and November 2019: 9 out of 13 received pembrolizumab and the remaining four underwent nivolumab. A median of 12 cycles (range, 3-16) of CPi therapy were infused. Thirteen patients underwent ASCT after CPi: 11 (84.6%) patients obtained a complete response (CR) and 2 had progression of disease, with an overall response rate of 84.6%. With a median follow-up of 3.3 years (range, 1.1-5.5), only one CR patient had disease relapse after 3.9 months from ASCT, leading to an estimated disease-free survival of 87.5% at 56.9 months. The estimated 5-year progression-free survival was 73.4% and overall survival was 92.3% at 4.8 years, respectively. No unexpected or cumulative toxicity was observed. Our results indicated that ASCT may represent a further effective therapeutic option as consolidation in HL after CPi treatment that today represents the last conventionally recognized therapeutic line.
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http://dx.doi.org/10.1002/hon.2803DOI Listing
December 2020

Effectiveness of chemotherapy after anti-PD-1 blockade failure for relapsed and refractory Hodgkin lymphoma.

Cancer Med 2020 11 2;9(21):7830-7836. Epub 2020 Sep 2.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Programmed death-1 (PD1) blockade is an efficient and safe therapeutic option in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, a substantial proportion of patients' progresses or loses the response to anti-PD1 treatment. We retrospectively investigated the effectiveness of salvage chemotherapies (CHT) for unsatisfactory response to anti-PD1, in 25 R/R cHL patients. Twenty-three patients (92%) were refractory to the last treatment before anti-PD1. After a median of 14 cycles (range 3-52), 68% (17/25) of patients had unsatisfactory responses to anti-PD1 therapy, whereas 6 had a partial response (PR) and 2 patients achieved complete response (CR), with an overall response rate (ORR) of 32%. After a median time of 1.5 months, 15 patients received a single agent treatment and 10 had a multi-agents regimen, due to the failure of PD1 blockade. The ORR was 60% (8 CR and 7 PR). Seven patients (3 in PR and 4 in CR) underwent a consolidation strategy with stem cell transplantation. Median progression-free survival (PFS) with salvage treatment was reached at 19.1 months, while median PFS after anti-PD1 has been reached at 8.2 months. After a median follow-up of 32.4 months, 6 patients died while 13 are still in CR. The median overall estimated from the start of CHT was not reached. The efficacy of treatment following anti-PD1 is not yet established, especially in lymphoma patients. To note, in our series, a subset of heavily pre-treated and chemo-refractory patients increased response rates to and survival with CHT given after exposure to immune-checkpoint inhibitors.
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http://dx.doi.org/10.1002/cam4.3262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643640PMC
November 2020

Erythroderma with brentuximab vedotin (skin side effects in mycosis fungoides).

J Dtsch Dermatol Ges 2021 Jan 27;19(1):99-102. Epub 2020 Jul 27.

Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1111/ddg.14197DOI Listing
January 2021

Impressive Continuous Complete Response after Mogamulizumab in a Heavily Pretreated Sézary Syndrome Patient.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020040. Epub 2020 Jul 1.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Background: Sézary syndrome (SS) is a rare lymphoproliferative neoplasm, almost incurable outside the setting of allogeneic transplantable patients. The prognosis for relapsed/refractory patients remains poor, as the available drugs confer short-lasting remission. In this setting, the anti-chemokine receptor type 4 (CCR4) monoclonal antibody mogamulizumab demonstrated efficacy in an international, open-label, randomized controlled phase 3 trial (MAVORIC) versus vorinostat.

Case Description: A heavily pretreated 57-year-old SS woman (stage IVA) was randomized in the mogamulizumab arm of MAVORIC at our Institution. She quickly achieved a response, but after 30 cycles, she was discontinued from therapy due to cutaneous toxicity. Nevertheless, she is still in complete response (CR).

Conclusions: mogamulizumab is an anti-CCR4 monoclonal antibody that can induce long-lasting response also in very heavily pretreated patients not responding to any previous treatment. The extraordinary characteristic of our patient is that she is still in CR after 2.5 years since treatment discontinuation.
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http://dx.doi.org/10.4084/MJHID.2020.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340218PMC
July 2020

Generation of pralatrexate resistant T-cell lymphoma lines reveals two patterns of acquired drug resistance that is overcome with epigenetic modifiers.

Genes Chromosomes Cancer 2020 11 30;59(11):639-651. Epub 2020 Jul 30.

Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York, USA.

While pralatrexate (PDX) has been successfully developed for the treatment of T-cell lymphoma, the mechanistic basis for its T-cell selectivity and acquired resistance remains elusive. In an effort to potentially identify synergistic combinations that might circumnavigate or delay acquired PDX resistance, we generated resistant cells lines over a broad concentration range. PDX-resistant cell lines H9-12 and H9-200 were developed, each exhibiting an IC50 of 35 and over 1000 nM, respectively. These lines were established in vitro from parental H9 cells. Expression analysis of the proteins known to be important determinants of antifolate pharmacology revealed increase expression of dihydrofolate reductase (DHFR) due to gene amplification, and reduced folate carrier1 downregulation, as the putative mechanisms of resistance in H9-12 and H9-200 cells. Cross resistance was only seen with methotrexate but not with romidepsin, azacitidine (AZA), decitabine, gemcitabine, doxorubicin, or bortezomib. Resistance to PDX was reversed by pretreatment with hypomethylating agents in a concentration-dependent fashion. Comparison of gene expression profiles of parental and resistant cell lines confirmed markedly different patterns of gene expression, and identified the dual specificity phosphatase four (DUSP4) as one of the molecular target of PDX activity. Reduced STAT5 phosphorylation following exposure to PDX was observed in the H9 but not in the H9-12 and H9-200 cells. These data suggest that combination with hypomethylating agents could be potent, and that DUSP4 and STAT5 could represent putative biomarkers of PDX activity.
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http://dx.doi.org/10.1002/gcc.22884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540375PMC
November 2020

Bendamustine-rituximab regimen in untreated indolent marginal zone lymphoma: experience on 65 patients.

Hematol Oncol 2020 Oct 29;38(4):487-492. Epub 2020 Jul 29.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

First line therapy of patients with marginal zone lymphomas (MZL) is not well established and various regimens with chemo-immunotherapy can be used. Rituximab plus bendamustine (BR) is an effective and manageable treatment option for patients affected by indolent non-Hodgkin lymphoma. The aim of this monocentric retrospective study was to analyze the effectiveness and safety of the use of BR regimen in MZL patients in first line in daily clinical practice. The treatment schedule was rituximab at the dose of 375 mg/m on day 1 of each cycle and bendamustine at the dose of 90 mg/m on day 2 and 3, every 28 days for a maximum of 6 cycles. We analyzed 65 MZL patients (28 extranodal [EMZL], 23 splenic [SMZL], and 14 nodal [NMZL]) who underwent BR regimen as first line treatment. The median time from diagnosis to therapy was 2.5 months. Final responses were: 38 complete response (CR, 58.5%), 20 partial response and 7 progressive disease, leading to an overall response rate (ORR) of 89.2%. With respect to the histology, the ORR was 89.3% for EMZL, 82.6% for SMZL and 100% for NMZL, respectively (difference not statistically significant). With a median follow-up time of 44.6 months (range, 3.3-175.0 months), 2 (one EMZL after 42 months and one SMZL after 10 months) of 38 (5.2%) CR patients had disease relapse, yielding an estimated disease free survival of 89.2% at 61.1 months. The estimated 6-year progression free survival was 71.8% with 15 relapsed/progressed patients showing lymphoma recurrence within 48 months from end of treatment. The most frequently reported adverse events (any grade) were neutropenia (N = 35, 53.8%), fatigue (N = 15, 23.0%), and nausea (N = 12, 18.4%). All toxicities quickly resolved and no treatment-related death occurred. The BR regimen is effective and feasible in MZL patients inducing prolonged disease control with manageable toxicities.
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http://dx.doi.org/10.1002/hon.2773DOI Listing
October 2020

Management of central nervous system relapse in a young patient affected by primary mediastinal large B-cell lymphoma: A case report.

Clin Case Rep 2020 Jun 8;8(6):933-937. Epub 2020 Apr 8.

Institute of Hematology "L. e A. Seràgnoli" University of Bologna Bologna Italy.

In primary mediastinal large B-cell lymphoma, central nervous system (CNS) relapse is an uncommon event with a dismal prognosis. We report about the successful management of CNS relapse with chemoimmunotherapy according to MATRix (methotrexate, cytarabine, thiotepa, and rituximab) protocol followed by autologous stem cell transplant.
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http://dx.doi.org/10.1002/ccr3.2706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303876PMC
June 2020

Elderly Non-GCB Diffuse Large B-Cell Lymphoma Patient Responding to Lenalidomide after Epicardial Relapse: A Case Report.

Acta Haematol 2020 11;143(6):594-597. Epub 2020 May 11.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy,

There is an unmet clinical need for elderly or unfit diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem cell transplantation. Lenalidomide is an immunomodulatory agent with antitumor activity in non-Hodgkin lymphoma, with an acceptable toxicity profile and manageable side effects. A 79-year-old Caucasian male with non-germinal center B-cell-like DLBCL achieved complete remission (CR) after first-line treatment with seven out of eight scheduled cycles of a polychemotherapy containing anthracycline, which had to be discontinued early due to the onset of atrial fibrillation. After 5 months, the patient had an early epicardial relapse. He underwent lenalidomide considering age, cardiological comorbidities, and chronic renal failure. After the third cycle, he achieved CR, confirmed at restaging after the sixth cycle of treatment. Lenalidomide was safe and well tolerated in a patient with atrial fibrillation developed after an anthracycline-based regimen and a relapse of the DLBCL. Moreover, this regimen was effective in a case with a rare extranodal involvement of the epicardium.
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http://dx.doi.org/10.1159/000505716DOI Listing
January 2021

Spontaneous remission of follicular lymphoma.

Hematol Oncol 2019 Dec 18;37(5):626-627. Epub 2019 Aug 18.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Follicular lymphoma is an indolent B cells proliferative disorder that represents approximately 35% of all non-Hodgkin lymphomas. Although spontaneous remission is uncommon in patients with low grade non-Hodgkin lymphomas, some cases have been reported. We present a case of follicular lymphoma for which we have documented a spontaneous remission both with serial instrumental investigations and through histological biopsy of the bone marrow. The patient is still in remission after 2 years of follow-up. The causes for a spontaneous remission are not known, and we can only hypothesize a possible reawakening of the host's immune response against the tumour.
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http://dx.doi.org/10.1002/hon.2653DOI Listing
December 2019

Lenalidomide in Pretreated Patients with Diffuse Large B-Cell Lymphoma: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice.

Oncologist 2019 09 2;24(9):1246-1252. Epub 2019 Apr 2.

Institute of Hematology, University of Bologna, Bologna, Italy

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency.

Subjects, Materials, And Methods: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice.

Results: One hundred fifty-three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow-up of 36 months, median overall survival was reached at 12 months and median disease-free survival was not reached at 62 months. At the latest available follow-up, 29 patients are still in response out of therapy. Median progression-free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation.

Conclusion: Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.

Implications For Practice: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.
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http://dx.doi.org/10.1634/theoncologist.2018-0603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738312PMC
September 2019

Histological findings in patients with suspected mediastinal lymphoma relapse according to positive positron emission tomography scan during follow-up: a large retrospective analysis in 96 patients.

Leuk Lymphoma 2019 09 1;60(9):2247-2254. Epub 2019 Mar 1.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna , Bologna , Italy.

Residual masses in patients with mediastinal lymphoma may be positron emission tomography (PET) positive during follow-up also in cases of complete response. The aim of this retrospective study is to verify the reliability of mediastinal PET-positive findings in suggesting disease relapse or progression during follow-up by histological verification. From January 2002 to March 2016, 96 patients with mediastinal lymphoma underwent PET follow-up after front-line treatment. A surgical biopsy was performed to confirm the suspected relapse (for a total of 113 procedures). A lymphoma relapse was diagnosed in 66/102 successful procedures (64.7%). Diagnosis at relapse was concordant with the initial diagnosis in all but 3 cases. Standardized uptake value was significantly higher among patients with relapse than among those who remained in remission (10 versus 5,  < .05). PET scan helps individuate patients with a high suspect of lymphoma relapse and may guide the surgeon to the most suitable target.
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http://dx.doi.org/10.1080/10428194.2019.1581931DOI Listing
September 2019

A case report of the long treatment experience of a Sézary syndrome responder patient: 16 years through all the systemic and innovative therapies.

Hematol Oncol 2019 Apr 30;37(2):202-204. Epub 2019 Jan 30.

Institute of Hematology "L. e A. Seràgnoli,", University of Bologna, Bologna, Italy.

Existing therapies for Sézary syndrome (SS) are limited in efficacy and in disease control, and patients have very poor prognosis. Here, we report a case report of a patient who has a 16-year history of SS and related treatments (both standard and experimental). In particular, two drugs, one conventional (gemcitabine) and one experimental (mogamulizumab), were able to induce long lasting response. Patient refused to undergo allogeneic stem cell transplantation. After eleven lines of therapeutic approaches, the patient is in very good partial response and free of therapy at the latest available follow-up.
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http://dx.doi.org/10.1002/hon.2573DOI Listing
April 2019

Italian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma.

Oncotarget 2018 May 4;9(34):23443-23450. Epub 2018 May 4.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.
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http://dx.doi.org/10.18632/oncotarget.25215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955107PMC
May 2018

Interesting activity of pegylated liposomal doxorubicin in primary refractory and multirelapsed Hodgkin lymphoma patients: bridge to transplant.

Hematol Oncol 2018 Apr 24;36(2):489-491. Epub 2018 Jan 24.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/hon.2492DOI Listing
April 2018

Impressive Response to Pixantrone after Allogeneic Transplant in a Multiple Relapsed Diffuse Large B-Cell Lymphoma.

Acta Haematol 2017 21;137(4):191-194. Epub 2017 Apr 21.

Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy.

Diffuse large B-cell lymphoma is the most frequent histology at diagnosis among non-Hodgkin B lymphomas and can be cured in 50-70% of cases after the first-line chemotherapy regimen. Patients who do not respond to first-line treatment can undergo numerous subsequent steps, culminating in allogeneic stem cell transplant (alloSCT). A relapse after alloSCT, however, carries an awful prognosis, seeing the demise of the patient usually in the following months. Here we present the case of a multiple relapsed patient who successfully underwent therapy with pixantrone after alloSCT, obtaining a complete remission without any considerable side effects.
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http://dx.doi.org/10.1159/000465511DOI Listing
July 2017

The treatment of primary mediastinal large B-cell lymphoma: a two decades monocentric experience with 98 patients.

BMC Cancer 2017 04 17;17(1):276. Epub 2017 Apr 17.

Institute of Haematology "L. e A. Seràgnoli", University of Bologna, Via Massarenti, 9 - 40138, Bologna, Italy.

Background: The purpose of this study is to investigate the most suitable first-line approach and the best combination treatment for primary mediastinal large B-cell lymphoma (PMLBCL) as they have been matter of debate for at least two decades.

Methods: Our single centre experience in the treatment of 98 de novo PMLBCL patients over the last 20 years is reviewed. All patients received MACOP-B chemotherapy. Thirty-seven received both rituximab and mediastinal radiotherapy; 30 were irradiated after chemotherapy, although not receiving rituximab and 20 received rituximab without radiotherapy consolidation. Eleven patients received chemotherapy only.

Results: Sixty-one (62.2%) patients achieved a complete response after MACOP-B (with or without rituximab); among the 27 (27.6%) partial responders, 21 obtained a complete response after radiotherapy. At the end of their scheduled treatment, 82 patients (83.7%) had a complete and 6 a partial response (6.1%). Eleven patients relapsed within the first 2 years of follow-up. The 17-year overall survival is 72.0% (15 patients died); progression-free and disease-free survival are 67.6% and 88.4%, respectively. A statistically significant difference in overall and progression-free survival was noted among treatment groups, although no disease-free survival difference was documented.

Conclusions: Our data indicate that a third-generation regimen like MACOP-B could be considered a suitable first-line treatment. Mediastinal consolidation radiotherapy impacts on survival and complete response rates and remains a good strategy to convert partial into complete responses. Data suggest that radiotherapy may be avoided in patients obtaining a complete response after (immuno)chemotherapy, but this requires confirmation with further ad hoc studies.
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http://dx.doi.org/10.1186/s12885-017-3269-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392963PMC
April 2017

Outpatient experience with biosimilar filgrastim in patients with lymphoid neoplasm: Lessons from daily clinical practice.

Hematol Oncol 2017 Dec 10;35(4):918-920. Epub 2016 Nov 10.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/hon.2371DOI Listing
December 2017

Long-Term Responders After Brentuximab Vedotin: Single-Center Experience on Relapsed and Refractory Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma Patients.

Oncologist 2016 12 2;21(12):1436-1441. Epub 2016 Aug 2.

Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy

Background: Brentuximab vedotin (BV) has shown high overall response rate in refractory/relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) with reported long-term response duration in clinical trials, but few data are available regarding its role in long-term outcomes in real life.

Patients And Methods: A single-center observational study was conducted on patients treated with BV in daily clinical practice to evaluate the long-term effectiveness of BV in HL and sALCL patients and to check whether clinical trial results are confirmed in a real-life context.

Results: The best response rate in the treated 53 patients (43 HL and 10 sALCL) was 69.8% (with 46.5% complete response [CR]) in HL and 100% (80% CR) for sALCL, respectively. With a median patient follow-up of 36.8 months, the estimated median duration of response was 31.5 months for HL and 17.8 for sALCL, respectively. At the latest available follow-up, 75% of patients were still in response, with 43% without any consolidation. Toxicity was primarily neurological and it was rarely so serious to require dose reduction or interruption. In addition, it always reversed completely after the end of treatment.

Conclusion: Our data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, for all patients who underwent stem cell transplantation immediately after BV, the procedure was consolidative. For patients who have remained in continuous CR without any consolidation after therapy, BV can induce prolonged disease control.

Implications For Practice: Brentuximab vedotin (BV) has shown a high overall response rate in refractory/relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma, with reported long-term response duration in clinical trials, whereas few data are available regarding its role in long-term outcomes in real life. The data reported in this study suggest that BV can induce the same results in daily clinical practice. The data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, BV can induce prolonged disease control in patients who have remained in continuous complete response without any consolidation after the drug.
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http://dx.doi.org/10.1634/theoncologist.2016-0112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153337PMC
December 2016

90-yttrium-ibritumomab tiuxetan consolidation of fludarabine, mitoxantrone, rituximab in intermediate/high-risk follicular lymphoma: updated long-term results after a median follow-up of 7 years.

Cancer Med 2016 Jun 14;5(6):1093-7. Epub 2016 Mar 14.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Radioimmunotherapy (RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in many studies RIT was represented by yttrium-90-ibritumomab tiuxetan ((90) Y-IT). Independently by the different front-line treatment, updates on the long-term follow-up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long-term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by (90) Y-IT as front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. With a median follow-up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long-term disease-free survival of 62.6%. The 7-year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second-line treatment. These data represented the first evidence of a real role even in the long period of 90Y-IT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma.
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http://dx.doi.org/10.1002/cam4.684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924367PMC
June 2016

High efficacy of the MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis, a 20 year experience.

BMC Cancer 2015 Nov 9;15:879. Epub 2015 Nov 9.

Department of Experimental, Diagnostic and Specialty Medicine- DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Background: Adult Langerhans cell histiocytosis (LCH) is an orphan disease. Chemotherapy is usually reserved to patients presenting with single system multifocal (SS-m) or multisystem (MS) disease but due to the lack of randomized studies no standard first line therapy has been defined yet. Pediatric regimens based on the vinblastine/prednisone backbone are not well tolerated in adults and probably less effective. We previously demonstrated high efficacy of the dose dense polichemotherapy regimen MACOP-B in 7 adult patients with SS-m or MS-LCH, in terms of high response rate and durable responses. Here we report an update of these data with the purpose of evaluating the long term efficacy of MACOP-B in adult LCH.

Methods: Clinical data of all adult LCH patients (n = 17) diagnosed and treated at our Institution during the past 20-year period were retrospectively reviewed.

Results: A total of 11 patients (6 with SS-m and 5 with MS-LCH) were treated with MACOP-B from 1995 to 2014. The overall response rate was confirmed to be 100 %, with a complete response of 73 % and a partial response rate of 27 %. Overall progression free survival was 64 %, and disease free survival after achievement of initial CR was 87 %. Overall survival rate was 82 % after 6.7 years of median follow-up.

Conclusions: These data confirm high activity of MACOP-B in adult LCH, indicating that a substantial fraction of patients achieve long lasting responses and can be cured with this therapeutic approach.
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http://dx.doi.org/10.1186/s12885-015-1903-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640159PMC
November 2015

Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma.

Exp Hematol Oncol 2015 27;4:24. Epub 2015 Aug 27.

Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.

Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies on TP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity.
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http://dx.doi.org/10.1186/s40164-015-0019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549912PMC
August 2015

Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma.

Oncotarget 2015 Mar;6(9):6553-69

Institute of Hematology and Medical Oncology L.A. Seragnoli, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy.

The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (γH2AX), marker of DNA damage and genomic instability. Constitutive γH2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466634PMC
http://dx.doi.org/10.18632/oncotarget.2720DOI Listing
March 2015

The role of rituximab and positron emission tomography in the treatment of primary mediastinal large B-cell lymphoma: experience on 74 patients.

Hematol Oncol 2015 Dec 25;33(4):145-50. Epub 2014 Sep 25.

Department of Nuclear Medicine, University of Bologna, Bologna, Italy.

Regarding primary mediastinal large B-cell lymphoma (PMLBCL), there are several controversial topics that warrant further investigation: the superiority of third-generation regimens, the impact of rituximab, the use of involved field radiotherapy (RT) and the assessment of clinical response by positron emission tomography (PET). We report our experience on 74 PMLBCL patients treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and rituximab: an observational retrospective single-centre study was conducted on patients diagnosed and treated between February 2002 and July 2011. All patients were evaluated by computed tomography scan and PET scan; after the final PET evaluation, PET-negative patients were observed, whereas PET-positive patients underwent mediastinal RT. Sixty-one (82.4%) patients achieved a complete response after the MACOP-B plus rituximab regimen; 68.9% presented a positive final PET and were treated with local RT, whereas 31.1% had a negative PET. Five patients relapsed within 12 months. At 10 years, overall survival was 82%, progression-free survival was 87.6% and disease-free survival (DFS) was 90.5% (median follow-up 4 years). No statistically significant differences were observed in DFS between the patients treated also with RT (PET positive) and patients only observed (PET negative): 90.7% vs 90% (p = 0.85), respectively. In our experience, adding rituximab does not change the final results in terms of complete response and DFS utilizing third-generation regimen. Furthermore, the introduction of the PET-guided RT approach leads to a patient-tailored treatment, which preserves the outcome and, at the same time, allows reducing the use of RT.
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http://dx.doi.org/10.1002/hon.2172DOI Listing
December 2015