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CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma.
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CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma.

Haematologica. 2018 Jan 19;:

Authors: Li Z, Ju X, Lee K, Clarke C, Hsu JL, Abadir E, Bryant CE, Pears S, Sunderland N, Heffernan S, Hennessy A, Lo TH, Pietersz GA, Kupresanin F, Fromm PD, Silveira PA, Tsonis C, Cooper WA, Cunningham I, Brown C, Clark GJ, Hart DNJ, Australia National Health and Medical Research Council Development Grant, Cancer Institute NSW Translationl Program Grant

Abstract
Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. We demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and interestingly, the trogocytosing CD83+T cells expressed significantly more PD-1 compared to CD83- T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T cell proliferation and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera and these returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non- human primates. No toxicity was observed but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma.

PMID: 29351987 [PubMed - as supplied by publisher]




Phase II study of oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma.
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Phase II study of oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma.

Haematologica. 2018 Jan 19;:

Authors: Van den Neste E, André M, Gastinne T, Stamatoullas A, Haioun C, Belhabri A, Reman O, Casasnovas O, Guesquieres H, Verhoef G, Claessen MJ, Poirel HA, Copin MC, Dubois R, Vandenberghe P, Stoian IA, Cottereau AS, Bailly S, Knoops L, Morschhauser F

Abstract
JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may thus be therapeutically beneficial in HL. This Phase II study assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in relapsed/refractory Hodgkin lymphoma patients. The primary objective was overall response rate according to IHP 2007 criteria. Thirty-three advanced patients (median prior lines: 5; refractory: 82%) were included; nine (27.3%) received at least 6 cycles of ruxolitinib and six (18.2%) > 6 cycles therapy. The overall response rate after 6 cycles was 3/32 (9.4%) patients, all partial responders, with transient stable disease in 11/32. Best overall response rate was 6/32 (18.8%). Rapid alleviation of B-symptoms was commonly noted. Median response duration was 7.7 months, median progression-free survival 3.5 months (95%CI: 1.9-4.6), and median overall survival 27.1 months (95%CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%); one led to treatment discontinuation; 87.5% recovered without sequelae. Twenty-five were of > Grade3. The latter consisted mostly of anemia (n=11) all considered related to ruxolitinib. Other main causes of > Grade3 adverse events included lymphopenia and infections. Of note, there was no Grade4 neutropenia or thrombocytopenia observed. Ruxolitinib shows signs of activity, though short-lived, beyond simple anti-inflammation. Its limited toxicity suggests the potential of being combined with other therapeutic modalities. ClinicalTrials.gov: NCT01877005.

PMID: 29351986 [PubMed - as supplied by publisher]




Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft versus host disease: low incidence of lower gastrointestinal tract disease.
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Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft versus host disease: low incidence of lower gastrointestinal tract disease.

Haematologica. 2018 Jan 19;:

Authors: Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, Hebert KM, Dunn R, Yim S, Johnson B, D'Souza A, Eapen M, Fenske TS, Hari P, Hamadani M, Horowitz MM, Rizzo JD, Saber W, Shah N, Shaw B, Pasquini M

Abstract
We conducted a phase 2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received Tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft versus host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range 22-76). All patients received busulfan-based conditioning, and were transplanted with HLA-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The median follow up for surviving patients was 15 months (range 9-20). The cumulative incidences of grades II-IV and III-IV acute graft versus host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1-16) at day 180, respectively. There was no difference in grades II-IV acute graft versus host disease in recipients that received myeloablative or reduced intensity conditioning regimens. Notably, there were no cases of graft versus host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft versus host disease (17% versus 45%, p=0.003) and a significant increase in grades II-IV acute graft versus host disease -free survival at 6 months (69% versus 42%, p=0.001) with Tocilizumab, tacrolimus and methotrexate which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with Tocilizumab, tacrolimus and methotrexate as T and B cell subsets recovered to near normal levels by 6-12 months post transplantation. We conclude that Tocilizumab has promising activity in preventing acute graft versus host disease, particularly in the lower gastrointestinal tract, and warrants further examination in a randomized setting.

PMID: 29351985 [PubMed - as supplied by publisher]




Venetoclax induced a complete response in a patient with AL amyloidosis plateaued on CyBorD.
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Venetoclax induced a complete response in a patient with AL amyloidosis plateaued on CyBorD.

Haematologica. 2018 Jan 19;:

Authors: Leung N, Thomé SD, Dispenzieri A

PMID: 29351984 [PubMed - as supplied by publisher]




Partial tandem duplication of KMT2A (MLL) may predict a subset of myelodysplastic syndrome with unique characteristics and poor outcome.
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Partial tandem duplication of KMT2A (MLL) may predict a subset of myelodysplastic syndrome with unique characteristics and poor outcome.

Haematologica. 2018 Jan 19;:

Authors: Choi SM, Dewar R, Burke PW, Shao L

Abstract
Partial tandem duplication (PTD) of the KMT2A (MLL) gene is a poor prognostic factor in acute myeloid leukemia, but its significance in the context of myelodysplastic syndrome (MDS) is unknown. Here, we used cytogenomic array to identify MLL-PTD in a group of MDS patients and compared their clinicopathologic characteristics with a cohort of high-risk MDS patients without MLL-PTD. We show that MLL-PTD defines a subset of MDS characterized by high blast count, normal karyotype, and extremely poor prognosis exceeding that of non-MLL-PTD high risk MDS, including those with complex karyotype. Survival of MLL-PTD patients did not exceed 17 months (median survival 9.85 months), except in the context of transplantation. Testing for MLL-PTD, which is not detectable using standard karyotype, may be more broadly considered in identifying this poor prognostic subgroup.

PMID: 29351983 [PubMed - as supplied by publisher]




Prevalence and characteristics of metabolic syndrome in adults from the French childhood leukemia survivors' cohort: A comparison with controls from the French population.
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Prevalence and characteristics of metabolic syndrome in adults from the French childhood leukemia survivors' cohort: A comparison with controls from the French population.

Haematologica. 2018 Jan 19;:

Authors: Oudin C, Berbis J, Bertrand Y, Vercasson C, Thomas F, Chastagner P, Ducassou S, Kanold J, Tabone MD, Paillard C, Poirée M, Plantaz D, Dalle JH, Gandemer V, Thouvenin S, Sirvent N, Saultier P, Béliard S, Leverger G, Baruchel A, Auquier P, Pannier B, Michel G

Abstract
The prevalence of the metabolic syndrome among adults from the French childhood acute leukemia survivors' cohort was prospectively evaluated considering the type of anti-leukemic treatment received, and compared with that of controls. The metabolic profile of those patients was compared with that of controls. 3203 patients from a French volunteer cohort were age- and sex-matched 3:1 to 1025 leukemia survivors (in both cohorts, mean age: 24.4 years, female individuals: 51%). Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III criteria. Metabolic syndrome was found in 10.3% of patients (mean follow-up duration: 16.3+/-0.2 years) and 4.5% of controls, (OR=2.49, p<0.001). Patients transplanted with total body irradiation presented the highest risk (OR=6.26, p<0.001); the other treatment groups also displayed a higher risk than controls, including patients treated with chemotherapy only. Odd ratios were 1.68 (p=0.005) after chemotherapy only, 2.32 (p=0.002) after chemotherapy and cranial irradiation, and 2.18 (p=0.057) in patients transplanted without irradiation. Total body irradiation recipients with metabolic syndrome displayed a unique profile compared with controls: smaller waist circumference (91 versus 99.6 cm, p=0.01), increased triglyceride levels (3.99 versus 1.5 mmol/l, p<0.001), fasting glucose levels (6.2 versus 5.6 mmol/l, p=0.049) and systolic blood pressure (137.9 versus 132.8 mmHg, p=0.005). By contrast, cranial irradiation recipients with metabolic syndrome had a larger waist circumference (109 versus 99.6 cm, p=0.007) than controls. Regardless of the anti-leukemic treatment, metabolic syndrome risk was higher among childhood leukemia survivors. Its presentation differed depending on the treatment type, thus suggesting divergent pathophysiology.

PMID: 29351982 [PubMed - as supplied by publisher]