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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has demonstrated its potential as a curative option for patients with r/r lymphoma. With the introduction of post-transplant cyclophosphamide-based (PTCY) graft-versus-host disease (GvHD) prophylaxis, allo-HCT using haploidentical related donors (Haplo-HSCT) has emerged as a valuable alternative for patients without an available HLA-matched donor. In this study, we compared intermediate and long-term outcomes between Haplo-HSCT and HLA-matched related donor (MRD) and unrelated donor (URD) transplantations in 16 matched pairs using age, disease status, lymphoma classification and performance status as matching criteria. Of note, 88% of patients in each group presented with active disease at the time of conditioning. After a median follow-up of >10 years, 10-year overall and progression-free survival and non-relapse mortality incidence after Haplo-HSCT were 31%, 25% and 38%, respectively, and did not differ compared to the values observed in MRD-HSCT and URD-HSCT. A remarkable lower incidence of acute GvHD ≥ II and moderate and severe chronic GvHD was observed after Haplo-HSCT compared to MRD-HSCT (50%/50%, p = 0.03/0.03) and URD-HSCT (44%/38%, p = 0.04/0.08), resulting in slightly higher 10-year GvHD-free and relapse-free survival (25%) and chronic GvHD-free and relapse-free survival (25%) in the Haplo-HSCT group. In conclusion, Haplo-HSCT is an effective treatment in patients with non-remission NHL. Given its advantage of immediate availability, haploidentical donors should be preferably used in patients with progressive disease lacking an HLA-matched related donor.

Background: Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma., Methods: We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 10 6 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m 2 intravenously on day 1, doxorubicin 50 mg/m 2 intravenously on day 1, vincristine 1·4 mg/m 2 [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m 2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m 2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation., Findings: Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab., Interpretation: Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma., Funding: Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome., Competing Interests: Declaration of interests A-KZ declares that this work was done before her employment at Janssen-Cilag. Opinions expressed are solely her own and do not express the views or opinions of her employer. A-KZ has received stock or stock options from Johnson & Johnson. KH has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Celgene, Servier, Sanofi, EUSA Pharma, and Hexal; has received support for attending meetings or travel, or both, from Roche, Celgene, and Sanofi; and has participated on a data safety monitoring board or advisory board from Roche, Celgene, Servier, EUSA Pharma, and Gilead. MT has received consultancy fees and research funding from Amgen, Roche, Regeneron, Kite, and Macrogenics. CS has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Janssen, and Norvatis; and support for attending meetings or travel, or both, from Bristol Myers Squibb, Roche, Novartis, and Kite Gilead. GL has received grants or contracts from AQUINOX, AGIOS, AstraZeneca, Bayer, Gilead, Janssen, Morphosys, Roche, and Verastem (grant to institution); consulting fees from Roche, Gilead, Janssen, Bayer, Bristol Myers Squibb/Celgene, Novartis, AstraZeneca, Takeda, NanoString, AbbVie, Incyte, Morphosys, Genmab, and Karyopharm; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Gilead, Janssen, Bayer, Bristol Myers Squibb/Celgene, Novartis, AstraZeneca, AbbVie and Incyte; payment for expert testimony from Morphosys; support for attending meetings or travel, or both, from Roche, Janssen, and Bristol Myers Squibb/Celgene; and participated on a data safety monitoring board or advisory board from Roche, Gilead, Janssen, Bayer, Bristol Myers Squibb/Celgene, Novartis, AstraZeneca, Takeda, Nanostring, Oncopeptides, AbbVie, Incyte, Morphosys, Genmab, and Karyopharm. JD has received personal fees from Janssen, Roche, AbbVie, Celgene, Takeda, and AstraZeneca. VV has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen; support for attending meetings or travel, or both, from Amgen and AbbVie; and participated on a data safety monitoring board or advisory board from Beigene, Gilead, and Bristol Myers Squibb. WK has received report grants from Roche, Amgen, Takeda, and Regeneron. WH has received support for the present manuscript in research funding from Roche. MD has received institutional research grants by AbbVie, Bayer, Celgene, Janssen, and Roche; honoraria for scientific advisory boards from AstraZeneca, Bayer, Beigene, Celgene, Genmab, Gilead, Incyte, Janssen, Novartis, and Roche; and speaker's honoraria from Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, and Roche. EH has received travel support for attending meetings or travel, or both, from Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The Follicular Lymphoma (FL) International Prognostic Index (FLIPI) and FLIPI-2 are well-described clinical risk models. Age >60 years at diagnosis is a risk factor in both scores. Recently, we showed that older age is not associated with higher risk of disease progression or inferior treatment efficacy. Instead, shorter survival of older patients results mainly from an increased risk of nonrelapse deaths. This questions the value of age as a meaningful component of scores intended to predict disease-specific survival. The newly proposed PRIMA-prognostic index (PRIMA-PI) only includes β2-microglobulin levels and bone marrow infiltration as risk factors. Here, we independently validate the PRIMA-PI in a clinical trial cohort of 475 patients with advanced FL who uniformly received cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone, and rituximab (R-CHOP) as frontline therapy. The PRIMA-PI separated 3 similar sized risk cohorts with 5-year progression-free survival (PFS) rates of 74%, 59%, and 39%, respectively ( P < .0001). Furthermore, we compare the PRIMA-PI with the FLIPI and FLIPI-2. We demonstrate that the PRIMA-PI has the highest specificity to identify high-risk patients (80% for 5-year PFS) because of its superior risk stratification in patients >60 years (73% vs 33% [FLIPI] and 47% [FLIPI-2] for 5-year PFS). Thus, the PRIMA-PI is a promising clinical tool to stringently identify patients at highest risk of poor outcome after frontline R-CHOP for advanced FL, and is particularly useful in patients with older age. Further validation in non-R-CHOP treated cohorts is needed., (© 2019 by The American Society of Hematology.)

Introduction: PI3K inhibitors are evaluated for relapsed and refractory Diffuse large B-cell lymphoma (DLBCL) patients., Objective: As rituximab has shown to influence B-cell receptor (BCR) signaling, we investigated the interaction of anti-CD20 antibody rituximab and the new type II glycoengineered anti-CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib., Methods: Established DLBCL cell lines were treated with either rituximab or obinutuzumab alone or in combination with PI3K delta inhibitor idelalisib., Results: Rituximab and to a lesser extent obinutuzumab monotherapy resulted in a temporary upregulation of p-Akt, p42/44, and p38 signaling pathways. Idelalisib reduced p-Akt expression. Rituximab antagonized the p-Akt downregulation at early time points, while obinutuzumab did not interfere with idelalisib's effects. In cell growth analysis, early antagonism could also be detected., Conclusion: The combination of idelalisib with CD antibodies shows an initial antagonism of rituximab but not obinutuzumab in downregulation of PI3K-signaling targets., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after ≥2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors' knowledge, there currently are no data regarding factors influencing transplantation outcomes., Methods: The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after ≥2 courses of induction chemotherapy., Results: Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively., Conclusions: Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL. Cancer 2017;123:1965-1970. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Adenovirus (ADV) infections can have a high mortality in immunocompromised patients and are difficult to treat., Objectives and Study Design: We retrospectively analyzed occurrence and risk factors of ADV infection in 399 adults with hematological disorders undergoing hematopoietic stem cell transplantation (allo-HSCT), focusing on alternative donor transplantation (ADT) and disseminated disease., Results: ADV infection occurred in 42 patients (10.5%). Disease was localized in 18 and disseminated in 6 patients. ADV infection was observed in 15% after ADT, performed in 29% of all recipients, and was less frequent (6%) in T-cell-replete (TCR) haploidentical transplantation using post-transplantation cyclophosphamide (PTCY) than in other ADT protocols. Lower age, the use of alternative donor grafts and acute graft-versus-host disease (GvHD)≥grade II were risk factors for ADV infection. After failure of standard antiviral treatment, three patients with disseminated ADV disease received one dose of ADV-specific T cells, resulting in virological response in 2/3 patients, clearance of ADV viremia in 2/2 patients, and survival of 1/3 patients; both patients with pneumonia died., Conclusions: ADV infection was of moderate occurrence in our adult recipients of allo-HSCT despite a high proportion of potential high-risk patients receiving ADT. TCR strategies using PTCY might limit ADV complications in haploidentical transplantation. Despite feasible adoptive therapy strategies, outcome of disseminated disease remains dismal., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011, the combination of rituximab with bendamustine (31 %) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide (22 %) regime. Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.

We retrospectively compared the incidence of virus infections and outcome in the context of immune reconstitution in two different HLA-haploidentical transplantation (haplo-HSCT) settings. The first was a combined T-cell-replete and T-cell-deplete approach using antithymocyte globulin (ATG) prior to transplantation in patients with hematological diseases (cTCR/TCD group, 28 patients; median age 31 years). The second was a T-cell-replete (TCR) approach using high-dose posttransplantation cyclophosphamide (TCR/PTCY group, 27 patients; median age 43 years). The incidence of herpesvirus infection was markedly lower in the TCR/PTCY (22 %) than in the cTCR/TCD group (93 %). Recovery of CD4+ T cells on day +100 was faster in the TCR/PTCY group. CMV reactivation was 30 % in the TCR/PTCY compared to 57 % in the cTCR/TCD group, and control with antiviral treatment was superior after TCR/PTCY transplantation (100 vs 50 % cTCR/TCD). Twenty-five percent of the patients in the cTCR/TCD group but no patient in the TCR/PTCY group developed PTLD. While 1-year OS was not different (TCR/PTCY 59 % vs cTCR/TCD 39 %; p = 0.28), virus infection-related mortality (VIRM) was significantly lower after TCR/PTCY transplantation (1-year VIRM, 0 % TCR/PTCY vs 29 % cTCR/TCD; p = 0.009). On day +100, predictors of better OS were lymphocytes >300/μl, CD3+ T cells >200/μl, and CD4+ T cells >150/μl, whereas the application of steroids >1 mg/kg was correlated with worse outcome. Our results suggest that by presumably preserving antiviral immunity and allowing fast immune recovery of CD4+ T cells, the TCR approach using posttransplantation cyclophosphamide is well suited to handle the important issue of herpesvirus infection after haplo-HSCT.

Prognosis is poor for patients with biologically aggressive Non-Hodgkin lymphoma (NHL), refractory to chemotherapy or relapsed after autologous transplantation, especially when no disease control before allogeneic transplantation is achieved. In 16 patients (median age 53, median prior regimes 5) with relapsed or refractory non-remission NHL, we analysed retrospectively the efficacy of a sequential therapy comprising clofarabine re-induction followed by a reduced-intensity conditioning with fludarabine, CY and melphalan, and T-cell-replete HLA-haploidentical transplantation. High-dose CY was utilized post-transplantation. All patients engrafted. Early response (day +30) was achieved in 94%. Treatment-related grade III-IV toxicity occurred in 56%, most commonly transient elevation of transaminases (36%), while there was a low incidence of infections (19% CMV reactivation, 19% invasive fungal infection) and GVHD (GVHD: acute III-IV: 6%; mild chronic: 25%). One-year non-relapse mortality was 19%. After a median follow-up of 21 months, estimated 1- and 2-year PFS was 56 and 50%, respectively, with 11 patients (69%) still alive after 2 years. In summary, sequential therapy is feasible and effective and provides an acceptable toxicity profile in high-risk non-remission NHL. Presumably, cytotoxic reinduction with clofarabine provides enough remission time for the graft-versus lymphoma effect of HLA-haploidentical transplantation to kick in, even in lymphomas that are otherwise chemo-refractory.

Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB=30-66%, ABC=45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB=16-38%, ABC=25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus+bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.

Haploidentical haematopoietic SCT (HSCT) using T-cell-replete grafts and post-transplant high-dose CY has found increasing acceptance. Our purpose was to evaluate the feasibility and outcome of this strategy as second HSCT incorporating donor change for acute leukaemia relapse after a first allogeneic transplantation. The courses of 20 consecutive adults (median age 37 years, 12 male) with AML (n=14), ALL (n=5) and acute bi-phenotypic leukaemia (n=1) were analysed retrospectively. Conditioning consisted of fludarabine, CY and either melphalan or TBI or tresosulfan+/-etoposide. Engraftment was achieved in 17 (85%), and a second remission was induced in 15 patients (75%) on day +30. The rate of grade II-IV acute GvHD was 35%, while chronic GvHD occurred in five patients. Most commonly observed grade III-IV toxicities were mucositis (30%), hyperbilirubinemia (20%), elevation of transaminases (20%) and creatinine (20%), while invasive fungal infection affected 30%. One-year non-relapse mortality (NRM) was 36%. At a median follow-up of 17 months, estimated 1-year OS was 45%, and 1-year relapse-free survival was 33%. This strategy was feasible and allowed for successful engraftment with a moderate rate of toxicity. Early outcome and NRM are at least comparable with results after a second HSCT from HLA-matched donors without donor change at HSCT2.

Clofarabine is a novel purine nucleoside analogue with immunosuppressive and anti-leukemic activity in acute lymphoblastic and myeloid leukemia (AML, ALL). This retrospective study was performed to evaluate the feasibility and anti-leukemic activity of a sequential therapy using clofarabine for cytoreduction followed by conditioning for haploidentical hematopoietic stem cell transplantation (HSCT) in patients with non-remission acute leukemia. Patients received clofarabine (5 × 30 mg/m² IV) followed by a T cell replete haploidentical transplantation for AML (n = 15) or ALL (n = 3). Conditioning consisted of fludarabine, cyclophosphamide plus either melphalan, total body irradiation or treosulfan/etoposide. High-dose cyclophosphamide was administered for post-grafting immunosuppression. Neutrophil engraftment was achieved in 83 % and complete remission in 78% at day +30. The rate of acute graft versus host disease (GvHD) grade II-IV was 22%, while chronic GvHD occured in five patients (28%). Non-relapse mortality (NRM) after 1 year was 23%. At a median follow-up of 19 months, estimated overall survival and relapse-free survival at 1 year from haploidentical HSCT were 56 and 39%, respectively. Non-hematological regimen-related grade III-IV toxicity was observed in ten patients (56%) and included most commonly transient elevation of liver enzymes (44%), mucositis (40%), and skin reactions including hand-foot syndrome (17%), creatinine elevation (17%), and nausea/vomiting (17%). The concept of a sequential therapy using clofarabine for cytoreduction followed by haploidentical HSCT proved to be feasible and allows successful engraftment, while providing an acceptable toxicity profile and anti-leukemic efficacy in patients with advanced acute leukemia. NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors.