Publications by authors named "Francesco Onida"

79 Publications

A case of aggressive systemic mastocytosis with bulky lymphadenopathy showing response to midostaurin.

Clin Case Rep 2021 Feb 29;9(2):978-982. Epub 2020 Dec 29.

Hematology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy.

Management of systemic mastocytosis is an emerging challenge which requires a multidisciplinary diagnostic approach and personalized treatment strategy. Midostaurin can rapidly reduce the disease burden, also in cladribine refractory cases.
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http://dx.doi.org/10.1002/ccr3.3717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869399PMC
February 2021

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications.

Front Immunol 2020 20;11:569381. Epub 2021 Jan 20.

Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy.

In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft--host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.
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http://dx.doi.org/10.3389/fimmu.2020.569381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854690PMC
January 2021

Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia.

Front Immunol 2020 19;11:584520. Epub 2021 Jan 19.

Hopital Saint-Louis, APHP, Université de Paris, Paris, France.

Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR-KIR-ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities.
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http://dx.doi.org/10.3389/fimmu.2020.584520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851088PMC
January 2021

Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia.

Hemasphere 2020 Dec 6;4(6):e497. Epub 2020 Nov 6.

Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy.

Atypical chronic myeloid leukemia (aCML) is a -negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in , and genes, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. To provide a comprehensive genomic characterization of aCML we applied a high-throughput sequencing strategy to 43 aCML samples, including both whole-exome and RNA-sequencing data. Our dataset identifies , , and as the most frequently mutated genes with a total of 43.2%, 29.7 and 16.2%, respectively. We characterized the clonal architecture of 7 aCML patients by means of colony assays and targeted resequencing. The results indicate that variants occur early in the clonal evolution history of aCML, while mutations often represent a late event. The presence of actionable mutations conferred both ex vivo and in vivo sensitivity to specific inhibitors with evidence of strong in vitro synergism in case of multiple targeting. In one patient, a clinical response was obtained. Stratification based on RNA-sequencing identified two different populations in terms of overall survival, and differential gene expression analysis identified 38 significantly overexpressed genes in the worse outcome group. Three genes correctly classified patients for overall survival.
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http://dx.doi.org/10.1097/HS9.0000000000000497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655091PMC
December 2020

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

Lancet Haematol 2020 Aug 18;7(8):e601-e612. Epub 2020 Jun 18.

Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.
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http://dx.doi.org/10.1016/S2352-3026(20)30205-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302757PMC
August 2020

Treatment of steroid resistant acute graft versus host disease with an anti-CD26 monoclonal antibody-Begelomab.

Bone Marrow Transplant 2020 08 13;55(8):1580-1587. Epub 2020 Mar 13.

Dipartimento di Oncoematologia Pediatrica, IRCCS, Ospedale Pediatrico Bambino Gesu', Sapienza, Università di Roma, Roma, Italy.

We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.
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http://dx.doi.org/10.1038/s41409-020-0855-zDOI Listing
August 2020

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party.

Haematologica 2021 Feb 1;106(2):375-383. Epub 2021 Feb 1.

Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France.

Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
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http://dx.doi.org/10.3324/haematol.2019.230128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849556PMC
February 2021

Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet.

Hemasphere 2018 12 29;2(6):e150. Epub 2018 Nov 29.

Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Chronic myelomonocytic leukemia (CMML) is a disease of the elderly, and by far the most frequent overlap myelodysplastic/myeloproliferative neoplasm in adults. Aside from the chronic monocytosis that remains the cornerstone of its diagnosis, the clinical presentation of CMML includes dysplastic features, cytopenias, excess of blasts, or myeloproliferative features including high white blood cell count or splenomegaly. Prognosis is variable, with several prognostic scoring systems reported in recent years, and treatment is poorly defined, with options ranging from watchful waiting to allogeneic stem cell transplantation, which remains the only curative therapy for CMML. Here, we present on behalf of the European Hematology Association and the European LeukemiaNet, evidence- and consensus-based guidelines, established by an international group of experts, from Europe and the United States, for standardized diagnostic and prognostic procedures and for an appropriate choice of therapeutic interventions in adult patients with CMML.
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http://dx.doi.org/10.1097/HS9.0000000000000150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745959PMC
December 2018

Acquired platelet dysfunction and overproduction of platelet cyclic AMP in two patients with myeloid malignancies.

Platelets 2019 26;30(8):1053-1056. Epub 2019 Jun 26.

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center , Milan , Italy.

The pathophysiology of impaired platelet function in acquired disorders is often poorly understood. We report two unrelated patients with hematologic malignancies associated with acquired severe bleeding diathesis, and complex platelet function abnormalities, including overproduction of the physiological inhibitor cyclic-AMP (cAMP). Patient 1, with mild macrocytic anemia and thrombocytopenia (100 x 10/L), was diagnosed with chronic myelomonocytic leukemia a few months after the onset of her bleeding diathesis and our analysis of platelet function. Patient 2, with bleeding diathesis of recent onset, was studied when his myelodysplastic syndrome with excess blasts had already progressed to acute myeloid leukemia. In both patients, platelet aggregation/ATP secretion, serum thromboxane B, intraplatelet content of ADP, ATP, serotonin, and fibrinogen were severely impaired. Baseline platelet cAMP levels were mildly elevated and markedly increased after stimulation by prostaglandin E. In conclusion, these are the first patients with myeloid malignancies associated with acquired severe platelet dysfunction and overproduction of cAMP.
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http://dx.doi.org/10.1080/09537104.2019.1636020DOI Listing
February 2020

Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions.

Haematologica 2019 10 2;104(10):1935-1949. Epub 2019 May 2.

Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
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http://dx.doi.org/10.3324/haematol.2019.222059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886439PMC
October 2019

Haploidentical Hematopoietic Stem Cell Transplant Complicated by Atypical Hemolytic Uremic Syndrome and Kidney Transplant From the Same Donor With No Immunosuppression but C5 Inhibition.

Transplantation 2019 02;103(2):e48-e51

Hematology and Bone Marrow Transplantation Unit, IRCCS S. Raffaele Scientific Institution, Milan, Italy.

Background: Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when complicating allograft hematopoietic stem cell transplant (HSCT). In the past, the outcome was very poor with the majority of patients reaching end-stage renal disease or dying with little or no chances of kidney transplant (KTx) due to the high risk of relapse. The availability of C5 inhibition has opened up significant therapeutic opportunities and has improved the outcome particularly if complement dysregulation (CD) is the underlying pathogenetic mechanism.

Methods: We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx received from the same donor thus performed without immunosuppression but anti-C5 inhibition.

Results: Soon after HSCT performed for acute lymphoblastic leukemia, the patient developed a TMA due to CD and reached end-stage renal disease. After 2 years on dialysis, the patient received a KTx from her father who was already the HSCT donor. Given the full chimerism, no immunosuppressive agent was prescribed except a short (2 days) course of steroids and eculizumab to prevent aHUS relapse. Nine months after the KTx, the patient is well with normal renal function, no immunosuppression and continues eculizumab prevention of aHUS (1 infusion every 21 days).

Conclusions: All patients with transplant-associated thrombotic microangiopathy should be screened for the causes of CD. C5 inhibition with eculizumab is an important therapeutic resource to manage this complication. When KTx is necessary, immunosuppression can be safely withhold in case of same donor for both grafts and documented full chimerism.
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http://dx.doi.org/10.1097/TP.0000000000002505DOI Listing
February 2019

Prospective evaluation of metabolic syndrome and its features in a single-center series of hematopoietic stem cell transplantation recipients.

Ann Hematol 2018 Dec 27;97(12):2471-2478. Epub 2018 Jul 27.

U.O.C. Oncoematologia, Servizio Trapianti di Midollo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.

Available studies on metabolic syndrome (MS) after hematopoietic stem cell transplantation (HSCT) are retrospective with heterogeneous inclusion criteria, and little is known about the early post-transplant phase. In our prospective study, clinical and laboratory data were collected in 100 HSCT recipients, 48 allogeneic and 52 autologous, at baseline, at + 30, + 100 and + 360 days. At baseline, MS was observed in 24 patients, significantly associated with insulin resistance and leptin on multivariate analysis. At + 30, the diagnosis of MS was confirmed in 43 patients, significantly related to insulin resistance and allogeneic transplants. If the whole series was considered, patients with MS had significantly higher mortality from any cause. The baseline presence of any MS feature was a predictor of + 30 MS. Isolated occurrences of MS features were related to hyperleptinemia and hyperinsulinemia, except in the case of low HDL cholesterol, linked to adiponectin and resistin. Our data confirm that patients undergoing HSCT have a high prevalence of MS, with hyperleptinemia playing a major role. The early peak of new MS cases is primarily attributable to insulin resistance, notably but not exclusively immunosuppression-induced; the subsequent long-term increase in MS cases may be an effect of persistent adipokine imbalance.
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http://dx.doi.org/10.1007/s00277-018-3452-0DOI Listing
December 2018

SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub.

Nat Commun 2018 06 6;9(1):2192. Epub 2018 Jun 6.

Department of Medicine and Surgery, University of Milano-Bicocca and San Gerardo hospital, 20900, Monza, Italy.

SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel-Giedion syndrome caused by SETBP1 mutations.
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http://dx.doi.org/10.1038/s41467-018-04462-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989213PMC
June 2018

Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation.

J Crohns Colitis 2018 Aug;12(9):1097-1103

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Background And Aims: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial.

Methods: We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries.

Results: Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56.

Conclusions: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.
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http://dx.doi.org/10.1093/ecco-jcc/jjy069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113702PMC
August 2018

Autologous Haematopoietic Stem Cell Transplantation (AHSCT) in Severe Crohn's Disease: A Review on Behalf of ECCO and EBMT.

J Crohns Colitis 2018 03;12(4):476-488

Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.

Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.
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http://dx.doi.org/10.1093/ecco-jcc/jjx184DOI Listing
March 2018

Models of Prognostication in Chronic Myelomonocytic Leukemia.

Authors:
Francesco Onida

Curr Hematol Malig Rep 2017 12;12(6):513-521

University of Milan - Dept. of Oncology and Hemato-Oncology Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Hematology/BMT Unit, Via Francesco Sforza no.35, 20122, Milan, Italy.

Purpose Of Review: Within the group of the myelodysplastic/myeloproliferative overlap neoplasms of the adult age, chronic myelomonocytic leukemia (CMML) is characterized by an extremely variable clinical course. This review aims to cover over the years main advancements in the identification of CMML clinical and biological features associated to survival outcomes and the consequent development of prognostic tools for individual patient treatment decision making.

Recent Findings: According to the last WHO classification of myeloid neoplasms, three subgroups of patients may be recognized on the base of percentage of blasts in marrow and in peripheral blood (CMML-0, CMML-1, and CMML-2), with corresponding decreasing life-expectations. Nonetheless, in each of the subgroups, prominent disparateness of biological characteristics associates to a large heterogeneity of clinical presentation, with very different prognostic implications. Recent findings indicate that the integration of clinical and molecular data appears to provide the most helpful prognostic information. Together with an orderly enlightenment for the increasing conception of specific disease characteristics, this review offers a comprehensive and thoughtful summary of the prognostic models developed over the last three decades for CMML.
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http://dx.doi.org/10.1007/s11899-017-0416-8DOI Listing
December 2017

New drugs and allogeneic hematopoietic stem cell transplantation for hematological malignancies: do they have a role in bridging, consolidating or conditioning transplantation treatment?

Expert Opin Biol Ther 2017 07 22;17(7):821-836. Epub 2017 May 22.

b A.O.U. Città della Salute e della Scienza di Torino, Department of Oncology and Department of Molecular Biotechnology and Health Sciences , University of Torino , Torino , Italy.

Introduction: Novel targeted therapies and monoclonal antibodies can be combined with allogeneic stem cell transplantation (allo-SCT) at different time-points: 1) before the transplant to reduce tumour burden, 2) as part of the conditioning in place of or in addition to conventional agents 3) after the transplant to allow long-term disease control. Areas covered: This review focuses on the current integration of new drugs with allo-SCT for the treatment of major hematological malignancies for which allo-SCT has been a widely-adopted therapy. Expert opinion: After having been used as single agent salvage treatments in relapsed patients after allo-SCT or in combination with donor lymphocyte infusions, many new drugs have also been safely employed before allo-SCT as a bridge to transplantation or after it as planned consolidation/maintenance. This era of new drugs has opened new important opportunities to 'smartly' combine 'targeted drugs and cell therapies' in new treatment paradigms that may lead to higher cure rates or longer disease control in patients with hematological malignancies.
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http://dx.doi.org/10.1080/14712598.2017.1324567DOI Listing
July 2017

Dose-Reduced Versus Standard Conditioning Followed by Allogeneic Stem-Cell Transplantation for Patients With Myelodysplastic Syndrome: A Prospective Randomized Phase III Study of the EBMT (RICMAC Trial).

J Clin Oncol 2017 Jul 2;35(19):2157-2164. Epub 2017 May 2.

Nicolaus Kröger, University Medical Center Hamburg-Eppendorf, Hamburg; Georg-Nikolaus Franke, University Hospital Leipzig, Leipzig; Uwe Platzbecker, University Hospital Dresden, Dresden; Kai Hübel and Christof Scheid, University of Cologne, Cologne; Thomas Weber, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle; Matthias Stelljes, University of Münster, Münster; Peter Dreger, University of Heidelberg, Heidelberg; Andreas Günther, University Hospital Schleswig Holstein Campus Kiel, Kiel; Wolfgang Bethge, University Hospital Tübingen, Tübingen; Guido Kobbe, Heinrich Heine University, Düsseldorf, Germany; Simona Iacobelli, Università Tor Vergata, Rome; Giorgio Lambertenghi Deliliers and Francesco Onida, Fondazione IRCC Ca' Granda Ospedale Maggiore Policlinico, University of Milano, Milan; Massimo Pini, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria; Stefano Guidi, Azienda Ospedaliera Universitaria Careggi, Florence, Italy; Ruzena Uddin, Guy's Hospital, London, United Kingdom; Marie Robin, Hôpital Saint Louis, Assistance Publique Hôpitaux Paris, France; Boris Afanasyev, SPB Pavlov Medical University, St Petersburg, Russia; Dominik Heim, University Hospital Basel, Basel Switzerland; Liisa Volin, Helsinki University Hospital, Helsiniki, Finland; Xavier Poiré, Cliniques Universitaires St-Luc, Brussels, Belgium; Marleen van Os, European Group of Blood and Marrow Transplantation Clinical Trials Office; Ronald Brand, Leiden University Medical Center, Leiden; and Theo de Witte, Radboud University Medical Center, Nijmegen, the Netherlands.

Purpose To compare a reduced-intensity conditioning regimen (RIC) with a myeloablative conditioning regimen (MAC) before allogeneic transplantation in patients with myelodysplastic syndrome (MDS) within a randomized trial. Patients and Methods Within the European Society of Blood and Marrow Transplantation, we conducted a prospective, multicenter, open-label, randomized phase III trial that compared a busulfan-based RIC with MAC in patients with MDS or secondary acute myeloid leukemia. A total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1:1 ratio and were stratified according to donor, age, and blast count. Results Engraftment was comparable between both groups. The CI of acute graft-versus-host disease II to IV was 32.3% after RIC and 37.5% after MAC ( P = .35). The CI of chronic graft-versus-host disease was 61.6% after RIC and 64.7% after MAC ( P = .76). The CI of nonrelapse mortality after 1 year was 17% (95% CI, 8% to 26%) after RIC and 25% (95% CI, 15% to 36%) after MAC ( P = .29). The CI of relapse at 2 years was 17% (95% CI, 8% to 26%) after RIC and 15% (95% CI, 6% to 24%) after MAC ( P = .6), which resulted in a 2-year relapse-free survival and overall survival of 62% (95% CI, 50% to 74%) and 76% (95% CI, 66% to 87%), respectively, after RIC, and 58% (95% CI, 46% to 71%) and 63% (95% CI, 51% to 75%), respectively, after MAC ( P = .58 and P = .08, respectively). Conclusion This prospective, randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia.
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http://dx.doi.org/10.1200/JCO.2016.70.7349DOI Listing
July 2017

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen.

Biol Blood Marrow Transplant 2017 Jul 5;23(7):1102-1109. Epub 2017 Apr 5.

Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Dept of Oncology, University of Milan, Milan, Italy.

The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500 mg/m). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.031DOI Listing
July 2017

Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Br J Haematol 2017 06 28;177(5):759-765. Epub 2017 Mar 28.

University Hospital Eppendorf, Hamburg, Germany.

Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates.
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http://dx.doi.org/10.1111/bjh.14619DOI Listing
June 2017

Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel.

Blood 2017 03 17;129(13):1753-1762. Epub 2017 Jan 17.

Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT.
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http://dx.doi.org/10.1182/blood-2016-06-724500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524528PMC
March 2017

Primary cutaneous B-cell lymphoma other than marginal zone: clinicopathologic analysis of 161 cases: Comparison with current classification and definition of prognostic markers.

Cancer Med 2016 10 26;5(10):2740-2755. Epub 2016 Sep 26.

Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Categorization of primary cutaneous B-cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus-based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL-LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL-NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a "double hit score" upon positivity for BCL2 and MYC. PCDLBCL-NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B-cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a "non-germinal B-cell" profile, whereas "germinal center" cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC-LT, which often coexpressed MYC and BCL2. The impact of single factors on 5-year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group-PCDLBCL-NOS-exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.
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http://dx.doi.org/10.1002/cam4.865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083727PMC
October 2016

Reactivation of Smac-mediated apoptosis in chronic lymphocytic leukemia cells: mechanistic studies of Smac mimetic.

Oncotarget 2016 Jun;7(26):39458-39472

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Dysfunctional apoptotic machinery is a hallmark feature of chronic lymphocytic leukemia (CLL). Accordingly, targeting apoptosis regulators has been proven a rational approach for CLL treatment. We show that CLL lymphocytes express high levels of XIAP, cIAP1, and cIAP2 compared to normal lymphocytes. Smac mimetic, Smac066, designed to bind to BIR3-domain of IAPs, induce apoptosis in primary CLL cells (n=71; p<0.0001), irrespective of prognostic markers. Apoptosis was mediated by diminished levels of IAPs (XIAP-p=0.02; cIAP-p<0.0001) and increased activation of caspases-8,-9,-3. The caspase-cleavage was in direct association with the levels of apoptosis (r2=0.8 for caspases-8,-9,-3). Correlative analysis revealed a direct relationship between reduction in IAPs and degree of apoptosis (r2=0.6 (XIAP); 0.5 (cIAP2)). There was a strong association between apoptosis, IAP-degradation, and concurrent caspase-activation. Pan-caspase inhibitor Z-Vad-fmk reversed the degradation of Mcl-1, but not IAPs suggesting that smac066 is selective to IAPs, however, Mcl-1 degradation is through caspase-mediated cleavage. Immunoprecipitation experiments revealed physical interaction between caspase-3 and XIAP that was disrupted by smac066. Importantly, XIAP and cIAP2 were markedly induced in bone-marrow and lymph-node microenvironments, providing a basis for IAP antagonists as anti-tumor agents in CLL. Smac066 synergized with ABT-737, revealing a mechanistic rationale to jointly target BH3 and BIR3 domains.
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http://dx.doi.org/10.18632/oncotarget.8462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129945PMC
June 2016

GvHD prophylaxis in non-haploidentical allogeneic peripheral blood stem cell transplantation: beyond the standard to prevent relapse in patients with high-risk chronic lymphoproliferative diseases?

Authors:
Francesco Onida

Eur J Haematol 2016 Jan;96(1):7-8

Hematology - BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy.

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http://dx.doi.org/10.1111/ejh.12593DOI Listing
January 2016

Romidepsin in relapsed/refractory T-cell lymphomas: Italian experience and results of a named patient program.

Leuk Lymphoma 2016 10 17;57(10):2370-4. Epub 2016 Feb 17.

a Institute of Hematology "L. E A. Seràgnoli", University of Bologna , Bologna , Italy ;

Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients.
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http://dx.doi.org/10.3109/10428194.2015.1137292DOI Listing
October 2016

Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial.

JAMA 2015 Dec;314(23):2524-34

Internal Medicine and Vascular Disease Unit AP-HP Hôpital Saint-Louis, Paris 7 University, France.

Importance: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease.

Objective: To evaluate the effect of autologous HSCT on refractory Crohn disease.

Design, Setting, And Participants: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids.

Interventions: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed.

Main Outcomes And Measures: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging.

Results: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died.

Conclusions And Relevance: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease.

Trial Registration: clinicaltrials.gov Identifier: NCT00297193.
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http://dx.doi.org/10.1001/jama.2015.16700DOI Listing
December 2015

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model.

J Clin Oncol 2015 Nov 5;33(32):3766-73. Epub 2015 Oct 5.

Julia J. Scarisbrick and Felicity Evison, University Hospital Birmingham, Birmingham; Richard Cowan, The Christie Hospital, Manchester; Stephen Morris and Sean J. Whittaker, St Thomas' Hospital, London, United Kingdom; H. Miles Prince and Robert Twigger, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Maarten H. Vermeer and Rein Willemze, Leiden University Medical Centre, Leiden, the Netherlands; Pietro Quaglino, Paolo Fava, and Milena Maule, University of Turin (Torino), Turin; Emilio Berti, Francesco Onida, and Laura Corti, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, University of Milano-Bicocca, Milan; Nicola Pimpinelli and Vieri Grandi, University of Florence, Florence; Alessandro Pileri and Annalisa Patrizi, University of Bologna, Bologna, Italy; Steven Horwitz and Christiane Querfeld, Memorial Sloan-Kettering Cancer Center, New York, NY; Pierluigi Porcu, Henry Wong, and Kelly Tyler, Ohio State University, Columbus, OH; Gary S. Wood, University of Wisconsin, Madison, WI; Francine Foss and Michael Girardi, Yale University, New Haven, CT; Joan Guitart, Timothy M. Kuzel, and Maria Estela Martinez-Escala, Northwestern University, Chicago, IL; Alain Rook and Ellen Kim, University of Pennsylvania, Philadelphia; PA; Christiane Querfeld, City of Hope Hospital, Duarte; Jinah Kim, Grant Ognibene, Shufeng Li, Mahkam Tavallaee, Richard T. Hoppe, and Youn H. Kim, Stanford University Medical Center, Stanford, CA; Rakhshandra Talpur and Madeleine Duvic, The University of Texas MD Anderson Cancer Center, Houston, TX; Rudolf Stadler and Rene Stranzenbach, Unit University Munster, Minden, Germany; Marie Beylot-Barry and Anne Pham-Ledard, Centre Hospitalier Universitaire Hospital de Bordeaux, Bordeaux; Martine Bagot, Laurence Michel, and Maxime Battistella, Hospital St Louis, Paris, France; Teresa Estrach, Hospital Clínico, University of Barcelona, Villarroel; Octavio Servitje and Cristina Muniesa,

Purpose: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers.

Patients And Methods: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS).

Results: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%).

Conclusion: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.
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http://dx.doi.org/10.1200/JCO.2015.61.7142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979132PMC
November 2015