The phase 2 LYSA study of prednisone, vinblastine, doxorubicin, and bendamustine for untreated Hodgkin lymphoma in older patients.

ABSTRACT: Older patients with classical Hodgkin lymphoma (cHL) require more effective and less toxic therapies than younger patients. In this multicenter, prospective, phase 2 study, we investigated a new firstline therapy regimen comprising 6 cycles of prednisone (40 mg/m2, days 1-5), vinblastine (6 mg/m2, day 1), doxorubicin (40 mg/m2, day 1), and bendamustine (120 mg/m2, day 1) (PVAB regimen) every 21 days for patients with newly diagnosed cHL aged ≥61 years with an advanced Ann Arbor stage. A Mini Nutritional Assessment score ≥17 was the cutoff value for patients aged ≥70 years. The primary end point was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88 years), with 35 patients (39%) aged ≥70 years. Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% confidence interval [CI], 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n = 11), toxicity during treatment (n = 4), secondary cancers (n = 6), or other causes (n = 3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P = .001), lymphopenia (P = .001), CRP (P = .0005), and comedications (P = .003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival end points were influenced by unrelated lymphoma events. This trial was registered at www.clinicaltrials.gov as #NCT02414568 and at EudraCT as 2014-001002-17.

Obinutuzumab versus Rituximab in transplant-eligible Mantle cell lymphoma patients.

Obinutuzumab (O) and Rituximab (R) are two CD antibodies that have never been compared in a prospective randomised trial in mantle cell lymphoma (MCL). Herein, we report the long-term outcome of the LYMA-101 (NCT02896582) trial, in which newly diagnosed MCL patients were treated with chemotherapy plus O before transplantation followed by O maintenance (O group). We then compared these patients to those treated with the same treatment design with Rituximab instead of O (R group) (NCT00921414). A propensity score matching (PSM) was used to compare the two populations (O vs R groups) in terms of MRD at the end of induction (EOI), PFS and OS. In LYMA-101, the estimated five-year PFS and OS since inclusion (n=85) were 83.4% (95%CI: 73.5-89.8%) and 86.9% (95%CI: 77.6-92.5%), respectively. At EOI, patients treated in the O group had more frequent bone marrow MRD negativity than those treated in the R group (83.1% vs 63.4% Chi2 p=0.007). The PSM resulted in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, the O group had a longer estimated five-year PFS (p=0.029; 82.8% versus 66.6%, HR 1.99, IC95 1.05-3.76) and OS (p=0.039; 86.4% versus 71.4% (HR 2.08, IC95 1.01-4.16) compared to the R group. Causes of death were comparable in the 2 groups, the most common cause being lymphoma. Obinutuzumab prior to transplantation and in maintenance provides better disease control and enhances PFS and OS, as compared to Rituximab in transplant-eligible MCL patients.

Extreme thrombocytosis with an aggressive evolution harboring a novel variant of calreticulin (CALR) in exon 3.

We describe the case of a patient with extreme thrombocytosis whose evolution was rapidly fatal. No cause of secondary thrombocytosis was found. There was no sign of myelofibrosis but the megakaryocytes were small and dysplastic. The patient presented a calreticulin (CALR) variant in exon 3 (C105S), as well as concomitant mutations of ASXL1, U2AF1, and EZH2. This variant of CALR has never been described before, and after sorting, all identified mutations were found in myeloid cells but not in lymphoid cells. Therefore, the diagnosis of a frontier case of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) was made. A treatment with hydroxycarbamide was started because of a high risk of thrombosis. Upon worsening of the hematological status two new mutations appeared, SETBP1 and ETV6, and the CALR mutation was still detectable, as well as the three other mutations found in the chronic stage. Our results show that this variant could contribute to MDS/MPN pathogenesis in that patient.

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of TP53 mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group.

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients aged over 65. We have now re-examined the classic prognostic factors, adding an assessment of the mutation status of TP53. Patients (n=74; median age 73 years) were treated with the RiBVD combination. Median Progression Free Survival (mPFS) was 79 months, and median Overall Survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level below 3.6 g/dL (Alb<3.6 g/dL) were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, p=0.014) was obtained for TP53mt versus TP53wt, and 3.6 (1.39-9.5, p=0.009) for Alb<3.6 g/dL vs Alb≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PFs: TP53mt (HR: 5.9 (1.77-19.5, p=0.004)), Alb<3.6 g/dL (HR: 5.2 (1.46-18.5, p=0.011)), and ECOG=2 (HR: 3.7 (1.31-10.6, p=0.014)). Finally, a score combining TP53 status and albumin level distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.

Features of non-Hodgkin's lymphoma diagnosed in minor salivary gland biopsies from primary Sjögren's syndrome patients.

OBJECTIVE: To evaluate the contribution of minor salivary gland biopsy (mSGB) histology in diagnosing primary SS (pSS)-associated non-Hodgkin B-cell lymphoma (NHL). METHODS: pSS patients with mSGB at NHL diagnosis were included. RESULTS: Among the 24 patients (92.3% female, mean age 61.3 years) with an mSGB at NHL diagnosis, 13 (54.2%) had mSGB histology-revealed NHL (mSGB+); it was the only site enabling NHL diagnosis in 10/13 (76.9%) patients. Mucosa-associated lymphoid tissue (MALT) lymphoma was found in 23/24 (95.8%) patients; 100% of mSGB+ identified MALT lymphomas. pSS and lymphoma characteristics were comparable for mSGB+ and mSGB- patients. Eight (61.5%) of the 13 mSGB+ patients and all 11 mSGB- patients were treated for lymphoma. Between diagnosis and 1 year of follow-up, the ESSDAI without the NHL item remained stable (7.4 vs 5.0; P = 0.33) for the five untreated patients, while it decreased significantly for the 19 treated patients (15.8 vs 5.1; P = 0.004). CONCLUSION: For pSS patients with suspected NHL, mSGB histology enabled NHL diagnosis in half of them, MALT was found in 95.8% and all mSGB+ were MALT lymphomas, thereby avoiding more invasive biopsy. Our results suggest that mSGB should be obtained at pSS diagnosis and repeated during follow-up when NHL is suspected.

Hidden in the Eyes-Recurrence of Systemic Hemopathies Reportedly "In Remission": Six Cases and Review of Literature.

Background and Objectives: Secondary ocular localizations of hematological malignancies are blinding conditions with a poor prognosis, and often result in a delay in the diagnosis. Materials and Methods: We describe a series of rare cases of ocular involvement in six patients with hematological malignancies, reportedly in remission, who presented secondary ocular localizations, challenging to diagnose. Two patients had an acute lymphoblastic leukemia (ALL) and developed either a posterior scleritis or a pseudo-panuveitis with ciliary process infiltration. One patient had iris plasmacytoma and developed an anterior uveitis as a secondary presentation. Two patients had a current systemic diffuse large B-cell lymphoma (DLBCL) and were referred either for intermediate uveitis or for papilledema and vitritis with secondary retinitis. Finally, one patient with an acute myeloid leukemia (AML) presented a conjunctival localization of a myeloid sarcoma. We herein summarize the current knowledge of ophthalmologic manifestations of extramedullary hematopathies. Results: Inflammatory signs were associated with symptomatic infiltrative lesions well displayed in either the iris, the retina, the choroid, or the cavernous sinus, from the admission of the patients in the ophthalmological department. These findings suggest that patients with ALL, AML, systemic DLBCL, and myeloma can present with ophthalmic involvement, even after having been reported as in remission following an effective systemic treatment and/or allograft. Conclusions: Early detection of hidden recurrence in the eyes may permit effective treatment. Furthermore, oncologists and ophthalmologists should be aware of those rare ocular malignant locations when monitoring patient's progression after initial treatment, and close ophthalmologic examinations should be recommended when detecting patient's ocular symptoms after treatment.

Integrated analyses of translatome and proteome identify the rules of translation selectivity in RPS14-deficient cells.

In ribosomopathies, the Diamond-Blackfan anemia (DBA) or 5q- syndrome, ribosomal protein (RP) genes are affected by mutation or deletion, resulting in bone marrow erythroid hypoplasia. Unbalanced production of ribosomal subunits leading to a limited ribosome cellular content regulates translation at the expense of the master erythroid transcription factor GATA1. In RPS14-deficient cells mimicking 5q- syndrome erythroid defects, we show that the transcript length, codon bias of the coding sequence (CDS) and 3'UTR (untranslated region) structure are the key determinants of translation. In these cells, short transcripts with a structured 3'UTR and high codon adaptation index (CAI) showed a decreased translation efficiency. Quantitative analysis of the whole proteome confirmed that the post-transcriptional changes depended on the transcript characteristics that governed the translation efficiency in conditions of low ribosome availability. In addition, proteins involved in normal erythroid differentiation share most determinants of translation selectivity. Our findings thus indicate that impaired erythroid maturation due to 5q- syndrome may proceed from a translational selectivity at the expense of the erythroid differentiation program, and suggest that an interplay between the CDS and UTR may regulate mRNA translation.

Successful nelarabine and venetoclax treatment of a relapsed/refractory mediastinal myeloid sarcoma with clonal TCR rearrangement.

Myeloid sarcomas represent a heterogeneous group of diseases with a tumoral presentation of acute myeloid leukemia. The clinical presentation of these hematologic cancers is typically aggressive and thus rapidly fatal in the absence of treatment, which relies on intensive chemotherapy that is sometimes followed by allogeneic hematopoietic stem-cell transplant (AHSCT). However, the global treatment strategy for these lesions is currently not well established. We report the case of a patient presenting with a highly refractory mediastinal myeloid sarcoma with uncommon morphologic and phenotypic characteristics and a clonal TCR rearrangement. The patient's disease was progressive despite multiple courses of intensive chemotherapy and a combination of nelarabine and venetoclax finally led to a complete metabolic response consolidated by an AHSCT. This treatment regimen, which has never been reported before, was very well tolerated especially on the neurologic and hematologic levels. This case underlines the clinical, histologic and molecular heterogeneity of what is called myeloid sarcoma and the importance of next-generation sequencing analysis of the tumor mass with both myeloid and lymphoid panels to better classify this rare entity and identify therapeutic targets.

Sequential mutational evaluation of CALR -mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression.

In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.

Mastocytosis onset in a patient with treated hairy cell leukemia: Just a coincidence?

Mastocytosis is a mast cell disease caused by functionally defective infiltrating mast cells and CD34+ mast cell precursors. The heterogeneous group of mast cell disorders is categorized into five variants in the updated 2017 World Health Organization (WHO) classification among those systemic mastocytosis with an associated neoplasm (SM-AHN). Except for myeloid neoplasia, lymphoproliferative disorders associated to SM-AHN are more scarce. Here, we report the second case ever described of associated mastocytosis and hairy-cell disease. A 38-year-old female patient without any specific medical history was diagnosed a hairy cell leukemia and BRAFV600E mutation was found in hairy cells. Since purine-analogs were avoided to prevent prolonged myelosuppression, she was treated with vemurafenib and rituximab. Despite early discontinuation due to vemurafenib-induced agranulocytosis, a partial response was observed. Strikingly, bone marrow biopsy performed one month after vemurafenib discontinuation revealed a nodular infiltration by 30% tumoral mastocytes. Along with elevated tryptase level, KITD816V mutation on mastocytes and clinical exam, the patient was diagnosed with systemic mastocytosis with an associated hematological neoplasm (SM-AHN). No BRAFV600E mutation was found on mastocytes. The physiopathology of this association is not known and might be only a coincidence or a common genetic driver mutation enhancing mast and hairy cells.

Whole genome copy number analysis in search of new prognostic biomarkers in first line treatment of mantle cell lymphoma. A study by the LYSA group.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin-embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan SNP-array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p(TP53) and 9p(CDKN2A) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression-free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q(CCDN1), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de-escalate treatment schedules or choosing targeted therapies or CART-cells.

Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.

CD13 expression in B cell malignancies is a hallmark of plasmacytic differentiation.

The diagnosis of Waldenström Macroglobulinaemia (WM)/lymphoplasmacytic lymphoma (LPL) remains one of exclusion because other B-cell lymphoproliferative disorders (B-LPD), such as marginal zone lymphoma (MZL), can fulfil similar criteria, including MYD88 L265P mutation. It has been suggested that expression of the myeloid marker CD13 (also termed ANPEP) is more frequent in LPL than in other B-LPD and has also been described on normal and malignant plasma cells. Here, CD13 expression was tested in a cohort of 1037 B-LPD patients from 3 centres by flow cytometry. The percentage of CD13-expressing cells was found to be variable among B-LPD but significantly higher in WM/LPL (median 31% vs. 0% in non-WM/LPL, P < 0·001). In multivariate linear regression, CD13 expression remained significantly associated with a diagnosis of WM/LPL (P < 0·001). A cut-off value of 2% of CD19+ cells co-expressing CD13 yielded the best diagnostic performance for WM/LPL assertion. This was further improved by association with the presence or absence of IgM paraprotein. Finally, given that previously published transcriptomic data revealed no difference in CD13 (also termed ANPEP) mRNA between normal and pathological B-cells, the hypothesis of some post-transcriptional regulation must be favoured. These results suggest that testing for CD13 expression in routine flow cytometry panels could help to discriminate WM/LPL from other B-LPD.

The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort.

BACKGROUND: The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care. METHODS: The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString® PanCancer IO360™ CodeSet using nCounter® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these. RESULTS: TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2). CONCLUSIONS: These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.

The role of radiotherapy as salvage and/or consolidation treatment in relapsed/refractory and high-risk diffuse large B-cell lymphoma.

OBJECTIVE: Many salvage therapies have been proposed for relapsed/refractory (R/R) diffuse large B-cell lymphomas or for consolidation in the case of suboptimal response. Radiotherapy (RT) is one modality of salvage therapy, but its place is currently not well defined. METHOD: This study reports a retrospective review of patients receiving unplanned radiotherapy for R/R diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL), or as consolidation therapy after second-line chemotherapy, treated in our hospital. RESULTS: Fifty-one patients with a median age of 53.5 years [19-89] were selected. The histologic type was DLBCL in 35 cases (68%), PMBCL in 8 cases (16%), and secondary transformed NHL in 8 cases (16%). Median aaIPI was 1 [0-4], and 17 patients (33%) had a high tumor burden (bulky disease). Sixteen patients (31%) were irradiated for a response considered to be insufficient, 18 patients (36%) were refractory, and 17 patients (33%) had relapsed. Patients were irradiated with a median dose of 40 Gy [15-44], 29 (57%) by a conformal 3D technique and 22 (43%) by tomotherapy. With a median follow-up of 36 months [1.0-127.8] after irradiation, 5-year progression-free survival (PFS) and overall survival (OS) were 62% and 72%, respectively. In multivariate analysis, adverse factors associated with PFS and OS in our cohort were age >70 years (HR = 5.06, P = .02) and post-RT relapse (HR = 12.24, P = .002), whereas favorable factors were number of lines of chemotherapy <3 (HR = 0.02, P = .03) and bulky disease (HR = 0.02, P = .009). CONCLUSION: Due to its low toxicity and ease of use, radiotherapy should therefore remain an available option in patients with R/R DLBCL or as consolidation therapy in patients with high-risk disease, mostly in patients with chemo-sensitive disease or bulky disease.