A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial.

The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) remains poor with current options. Here we prospectively evaluated the combination of pixantrone with obinutuzumab for up to six cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary end-point. Sixty-eight patients were evaluated, median age was 75 years, median number of prior lines was three (range 1-10), 52 patients (76.5%) were diagnosed with DLBCL and 16 (23.5%) patients had transformed indolent lymphoma or follicular lymphoma (FL) IIIB. ORR was 35.3% for all and 40% for evaluable patients (16.6% complete response), median progression-free survival (PFS) and overall survival (OS) were 2.8 months and 8 months, respectively. Analysis of the cell of origin revealed a superior course for patients with non-GCB (germinal centre B-cell-like) phenotype [median OS not reached (n.r.) vs 5.2 months]. Patients with one prior line had an improved outcome over patients treated in later lines (PFS n.r. vs 2.5 months). Disease progression was the main reason for premature termination. Adverse events were mainly haematologic. The combination treatment revealed no unexpected adverse events. Most relevant non-haematologic toxicity was infection in 28% of patients. In summary, pixantrone-obinutuzumab showed clinical activity with sometimes long-term remission; however, the trial failed to meet its primary end-point.

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

BACKGROUND: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. METHODS: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. FINDINGS: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. INTERPRETATION: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. FUNDING: Deutsche Krebshilfe.

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1-200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma.

Health-related quality of life was a secondary endpoint in the phase III GALLIUM study in previously untreated patients with follicular lymphoma who were treated with rituximab- or obinutuzumab-chemotherapy. Patients were randomized 1:1 to receive induction therapy with obinutuzumab- or rituximab-chemotherapy and maintenance in responders. Health-related quality of life was assessed using the Functional Assessment of Cancer Treatment-Lymphoma questionnaire, incorporating well-being and lymphoma-specific subscales. Assessments were performed at baseline, and during induction, maintenance, and follow-up (maximum 84 months). Clinically meaningful responses were defined by minimally important difference values. Of 1202 randomized patients (median follow-up 57.4 months), 557/601 (92.7%; obinutuzumab-chemotherapy) and 548/601 (91.2%; rituximab-chemotherapy) completed all Functional Assessment of Cancer Treatment-Lymphoma scales at baseline. Mean baseline health-related quality of life scores were similar between both arms, with all patients having some functional impairment and lymphoma symptoms. Over the course of treatment, mean health-related quality of life remained similar in both arms. Equal proportions of patients in both arms achieved minimally important difference by the Functional Assessment of Cancer Treatment-Lymphoma lymphoma-specific subscale and summary scales throughout induction, maintenance, and follow-up. On each summary scale, ~ 50% of patients in each arm achieved minimally important difference by maintenance month 2. In GALLIUM, similar improvements in health-related quality of life were seen with obinutuzumab- and rituximab-chemotherapy, suggesting that both treatments reduced lymphoma-related symptoms, and treatment-related side effects did not abrogate these improvements in well-being. ClinicalTrials.gov identifier: NCT01332968.

Serological hepatitis B virus (HBV) activity in patients with HBV infection and B-cell non-Hodgkin's lymphoma.

BACKGROUND: Previous epidemiological studies suggest an association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (B-NHL). The aim of our study was to evaluate clinical characteristics and serological indicators of HBV activity in patients who were diagnosed with both HBV infection and indolent or aggressive B-NHL. METHODS: Seventy-two patients with current or resolved HBV infection and B-NHL were identified between 2000 and 2017 at our institution. RESULTS: Forty-five (63%) and 27 (37%) patients were identified with aggressive and indolent B-NHL, respectively. In indolent B-NHL, the proportion of HBsAg-positive patients was significantly higher compared with aggressive B-NHL (59% vs 38%, P = .03). HBV-DNA levels were significantly higher in patients with indolent compared to aggressive B-NHL (P = .01). In the subgroup analyzes of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the rate of HBsAg positivity in FL is significantly higher than that in DLBCL (83% vs 44%, P = .04), and HBV-DNA levels were significantly higher in FL compared with DLBCL (P = .007). CONCLUSION: Our results suggest that serological HBV activity is higher in patients with both HBV infection and indolent B-NHL compared to those with aggressive B-NHL.

Role of virological serum markers in patients with both hepatitis B virus infection and diffuse large B-cell lymphoma.

BACKGROUND: Causality between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression-free survival (PFS) in patients with both HBV infection and DLBCL. METHODS: In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co-infection were excluded from this study. We retrospectively analyzed patients' demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA) on OS and PFS. RESULTS: The majority of patients (n = 21, 62%) had advanced disease stage (III/IV) at diagnosis. In the first-line therapy, 24 patients (70%) were treated with R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti-HBe positive patients had a statistically significant better OS and PFS compared with anti-HBe negative group (both P < .0001). Viremia with HBV-DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001). CONCLUSION: High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL.

Orchestration of Chemomobilization and G-CSF Administration for Successful Hematopoietic Stem Cell Collection.

Successful collection of peripheral blood stem cells (PBSCs) depends on the optimal orchestration of mobilization chemotherapy, granulocyte colony stimulating factor (G-CSF) application, and CD34+ cell number assessment in the peripheral blood (PB). However, determining the optimal timing in accordance to the applied chemomobilization regimen can be challenging. Although most centers apply their own local timing schedules, a reliable timetable including the currently most often used mobilization regimens is lacking. We present a comprehensive analysis of the timing modalities for 11 of the most commonly used chemomobilization regimens. A retrospective analysis was performed on the clinical and PBSC collection parameters (including duration of G-CSF application, time point of CD34+ assessment, PB CD34+ cell count, number of leukapheresis [LP] sessions, processed blood volume, and CD34+ collection results) of 91 representatively selected patients who had undergone stem cell mobilization at 2 collection centers. Six to 10 patients were analyzed per regimen with a variety of diagnoses, including multiple myeloma, malignant lymphoma, and sarcoma. No collection failures (<2 × 106 CD34+ cells/kg body weight) were observed. All analyzed patients successfully reached their individual collection goal in adherence to the given schedule of chemotherapy, application of G-CSF, measurement of CD34+ cells, and subsequent LP. The presented data on the timing of chemomobilization, G-CSF application, and stem cell collection may be helpful in clinical decision making and contribute to a more transparent and predictable treatment process.

The impact of stem cell transplantation on the natural course of peripheral T-cell lymphoma: a real-world experience.

The role of autologous stem cell transplantation (autoSCT) as consolidating treatment for peripheral T-cell lymphoma (PTCL) is unsettled. The aim of this analysis was to investigate the impact of autoSCT in the upfront setting by intent-to-treat and to study salvage strategies after relapse. Retrospective follow-up of all patients aged 18-70 years and treated at our institution for ALK-PTCL diagnosed between 2001 and 2014. Of 117 eligible patients, diagnosis was PTCL-NOS in 34, ALCL ALK- in 31, AITL in 28, and other PTCL in 24 patients. Disregarding 20 patients who received first-line treatment externally, upfront autoSCT was not intended in 34 due to comorbidity, higher age, low IPI, physician's decision or unknown reasons (nITT), while intent-to-transplant (ITT) was documented in 63 patients. ITT was not associated with significant benefits for 5-year progression-free survival (PFS) and overall survival (OS) with 46 and 23% in the ITT group vs. 42 and 25% in the nITT group, even after multivariate adjustment for confounders. Altogether, 91 of all 117 patients relapsed or progressed. Thirty-one patients managed to proceed to salvage allografting and achieved a 5-year OS of 52%. In contrast, all 7 patients receiving salvage autoSCT relapsed and died, and only 3 of the 51 patients not eligible for SCT salvage survived. In this study, a significant benefit of intending first-line autoSCT over non-transplant induction in patients with ALK-PTCL did not emerge. Most patients fail first-line treatment and have a poor outlook if salvage alloSCT cannot be performed.

NKT cells - New players in CAR cell immunotherapy?

Low levels of peripheral blood natural killer T (NKT) cells in cancer patients and a favorable outcome associated with a high number of tumor-infiltrating NKT cells demonstrated in several studies indicated the important role of these immune cells in the antitumor response. With effective antitumor immunity via direct tumor lysis, cytokine modulation of effector cells and regulation of immunosuppressive cells, type I NKT cells display interesting features/properties for the rapidly developing chimeric antigen receptor (CAR) technology. Due to their restriction to the monomorphic HLA-like molecule CD1d, but not to the polymorphic human leukocyte antigen (HLA), NKT CAR cells show potential for enabling autologous and allogeneic/off-the-shelf cancer immunotherapy. Promising results were obtained in preclinical NKT CAR cell studies, but clinical trials have not yet been conducted. In this review, we summarize the biological features of NKT cells, their role in antitumor immunity and recent advances in the development of NKT CAR cells.

Selective contrast-enhanced computed tomography is appropriate in diffuse large B-cell lymphoma therapy response assessment.

OBJECTIVE: Although not the gold standard, contrast-enhanced CT of neck, thorax, and abdomen/pelvis is routinely performed in diagnosis and response assessment of DLBCL. PD during first-line treatment is a relatively rare event. The question arises if the imaging of initially involved regions only might be sufficient for response evaluation. METHOD: We retrospectively analyzed the data of 167 DLBCL patients who had an extensive contrast-enhanced CT scan at first diagnosis. The majority of patients (n = 128, 77%) was treated with R-CHOP. Therapy response was assessed as interim and end of treatment staging by contrast-enhanced CT. RESULTS: The overall response rate at the end of treatment was 94%. None of the patients showed involvement of new sites at interim staging. As a major finding, none of the patients showed an involvement of sites, which were not initially involved. Four patients developed PD during first-line chemotherapy/after mid-treatment staging and 31 relapsed. A conclusive comparison between initial and PD/relapse DLBCL involvement was possible in 27 patients: 8 patients did and 19 patients did not show additional/new sites of involvement compared to first diagnosis. CONCLUSION: Our retrospective analysis provides a rationale for selective imaging of initially involved DLBCL sites for therapy response assessment.

Outcome after high-dose chemotherapy and autologous stem cell transplantation in patients with aggressive B-cell non-Hodgkin's lymphoma.

OBJECTIVE: For more than two decades, high-dose chemotherapy (HDT) and autologous blood stem cell transplantation (ABSCT) were treatment options for patients with aggressive B-cell non-Hodgkin's lymphoma (B-NHL). However, the ideal timing and the collective patient benefits are still being debated. METHOD: We retrospectively analyzed the data of 163 patients with B-NHL who received an HDT protocol followed by ABSCT between 2001 and 2007. Patients were analyzed according to the time point of HDT/ABSCT to compare upfront (directly after induction, n = 72, 44%) versus secondary transplantation (at first relapse, n = 91, 56%). RESULTS: The overall response rate was 100% and 94% after upfront and secondary HDT/ABSCT, respectively. No significant differences were found for hematopoietic recovery and toxicity profile. The progression-free survival (PFS) and overall survival (OS) probability were found to be significantly higher in the upfront HDT/ABSCT treatment group (P = .018 and P = .004). In multivariate analysis, upfront HDT/ABSCT and low IPI risk score had a significant beneficial effect on OS (P = .031 and P = .019). CONCLUSION: HDT and ABSCT directly after induction chemotherapy were confirmed to be feasible with high PFS and OS rates. In addition, for patients with relapse after first-line therapy and consecutively poor prognosis, HDT/ABSCT also offers an effective treatment strategy.

Acalabrutinib, A Second-Generation Bruton's Tyrosine Kinase Inhibitor.

The Bruton's tyrosine kinase (BTK) is an essential in the B-cell receptor (BCR) signaling pathway which was identified as crucial in the pathogenesis of B-cell malignancies. Ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of distinct B-cell malignancies. To overcome off-target side effects of and emerging resistances to ibrutinib, more selective second-generation BTK inhibitors were developed. Acalabrutinib is a novel second-generation BTK inhibitor and has shown promising safety and efficacy profiles in phase 1/2 clinical trials in patients with relapsed CLL and pretreated MCL. Recently, acalabrutinib was approved by the FDA for treatment of adult patients with MCL who received at least one prior therapy. However, clinical trials on a direct comparison between ibrutinib and acalabrutinib and on combination treatment options with other agents as CD20 antibodies are warranted.

Ibrutinib.

Abnormal B-cell receptor (BCR) signalling is a key mechanism of disease progression in B-cell malignancy. Bruton's tyrosine kinase (BTK) has a pivotal role in BCR signalling. Ibrutinib (PCI-32765) is a small molecule which serves as a covalent irreversible inhibitor of BTK. It is characterized by high selectivity for BTK and high potency. Ibrutinib is currently approved by the FDA and EMA for use in chronic lymphocytic leukaemia in any line of treatment, for treatment of Waldenstrom macroglobulinemia in patients who have received previous treatments or are not suitable to receive immunochemotherapy as well as for second line treatment of mantle cell lymphoma and for patients with marginal zone lymphoma who have received at least one prior anti-CD20-based therapy. In addition, there is emerging clinical data on its efficacy in ABC subtype diffuse large B-cell lymphoma, multiple myeloma and primary central nervous system lymphoma. Ibrutinib has opened new options for treatment of those patients that have relapsed or have been refractory to more classical modes of treatment. Moreover, Ibrutinib has been shown to be effective in patients that have been known to have little sensitivity to classical immunochemotherapy. Having a favourable risk profile, the substance is, unlike conventional immunochemotherapy, also suitable for the less physical fit patients. Cases of primary and secondary resistance to Ibrutinib have emerged and there is an ongoing effort to identify their mechanism and develop strategies to overcome them. Beyond its direct effects on survival and apoptosis of malignant B-cells, there is increasing evidence that Ibrutinib is able to modulate the tumour microenvironment to overcome mechanisms of immune evasion. This has sparked interest in use of the substance beyond lymphoid malignancy. This chapter discusses structure, mechanism of action and toxicities of Ibrutinib and also presents important preclinical and clinical data as well as mechanisms of Ibrutinib resistance. Combination strategies with immunotherapeutic strategies such as immune checkpoint blockade and CAR T-cell therapy may be synergistic and are currently under investigation.

Storage Duration of Autologous Stem Cell Preparations Has No Impact on Hematopoietic Recovery after Transplantation.

Peripheral blood stem cells (PBSCs) are widely used for autologous blood stem cell transplantation (ABSCT). These cells must be stored for months or even years, usually at temperatures ≤-140°C, until their use. Although several in vitro studies on CD34+ viability and clonogenic assays of PBSCs after long-term storage have been reported, only a few publications have investigated the influence of long-term storage on in vivo hematopoietic reconstitution. In this study, we retrospectively analyzed hematopoietic recovery after storage of PBSCs via controlled-rate freezing (CRF) and cryostorage in 10% DMSO at ≤-140°C in 105 patients with multiple myeloma who received high-dose melphalan before ABSCT. Three groups of PBSC transplantation (n = 247) were delineated based on the storage period: short-term (≤12 months, n = 143), medium-term (>12 and ≤60 months, n = 75), and long-term storage (>60 months, n = 29). A neutrophil increase of ≥.5 × 109/L in medium-term or long-term PBSC cryopreservation groups was observed at day 14 after ABSCT; this increase was comparable to patients who received briefly stored PBSCs (day 15). No negative effect of PBSC storage duration was observed on leucocyte or neutrophil reconstitution. Platelet reconstitutions of ≥20 × 109/L and 50 × 109/L were observed after median times of 10 to 11 and 13 to 14 days after ABSCT, respectively. No influence of PBSC storage duration on platelet recovery of ≥20 × 109/L and ≥50 × 109/L was observed in the 3 storage groups (P = .07, P = .32). The number of previous ABSCTs also had no significant impact upon hematopoietic reconstitution. In conclusion, these results indicate that long-term cryopreservation of PBSC products at vapor nitrogen temperature after CRF does not have a negative effect on hematopoietic recovery even after prolonged storage.

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

BACKGROUND: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. METHODS: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). FINDINGS: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). INTERPRETATION: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. FUNDING: Janssen Research & Development, LLC.

Analysis of prognostic factors in patients with newly diagnosed diffuse large B-cell lymphoma and skeletal involvement.

BACKGROUND: Skeletal involvement (SI) is observed at low prevalence in patients with diffuse large B-cell lymphoma (DLBCL). Due to the rareness of this particular condition, prospective trials for these patients are scarce. METHODS: We analyzed clinical characteristics and outcome of 75 patients with DLBCL and SI in order to identify factors with prognostic impact towards progression-free survival (PFS) and overall survival (OS). RESULTS: Limited stage disease (Ann Arbor stage IE-IIE) was present in 34 patients (45%), 41 patients (55%) had advanced stage disease (Ann Arbor stage IIIE-IVE). Outcome was generally favorable for patients with DLBCL and SI with 3-year OS of 83%. The international prognostic index (IPI) was able to distinguish between different risk groups within this specific entity. Additionally, hypercalcemia showed to be a factor significantly associated with inferior survival. In regard to first-line treatment modalities, consolidative radiotherapy was positively associated with prolonged PFS and OS while intensification of chemotherapy had no significant impact. CONCLUSIONS: In our cohort of patients with DLBCL and SI, high-risk IPI as well as presence of hypercalcemia were associated with inferior outcome. Consolidative radiotherapy had a positive impact on survival.

High-dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting.

BACKGROUND: High-dose (HD) chemotherapy with melphalan and autologous blood stem cell transplantation (ABSCT) for treatment of symptomatic multiple myeloma (MM) on an outpatient basis has been well established in the USA and Canada, whereas in Germany and Western Europe an inpatient setting is the current standard. We report on a German single-centre program to offer the procedure on an outpatient basis to selected patients. METHODS: Major requirements included: patients had to have family and/or other caregivers, had to be able to reach the hospital within 45 min and have an ECOG performance score of 0-1. Patients with severe co-morbidities were not included. RESULTS: From September 2012 until April 2016, 21 patients with MM stage IIIA were enrolled. All engrafted within the expected time range (median 14 days), and no severe adverse events occurred. 14 patients (67%) had an episode of neutropenic fever and blood cultures were positive in 4 patients (19%). Although rather liberal criteria for hospital admission were applied, 14 patients (67%) were treated entirely on an outpatient basis. CONCLUSIONS: HD chemotherapy and ABSCT on an outpatient basis is safe and feasible if it is conducted in an elaborate surveillance program. The feedback from patients was very positive, thus encouraging further expansion of the program.

Comparison of biosimilar filgrastim, originator filgrastim, and lenograstim for autologous stem cell mobilization in patients with multiple myeloma.

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) originators such as filgrastim (Neupogen) and lenograstim (Granocyte) are widely used for peripheral blood stem cell (PBSC) mobilization. In recent years, biosimilar agents have been approved for the same indications. The aim of this retrospective study was to compare the mobilization efficiency of the three G-CSF variants originator filgrastim, lenograstim, and the biosimilar Filgrastim Hexal in a homogeneous group of multiple myeloma (MM) patients in first-line therapy. STUDY DESIGN AND METHODS: Overall mobilization data of 250 patients with MM were included. Of these patients, 74 (30%), 131 (52%), and 45 (18%) were mobilized with originator filgrastim, biosimilar Filgrastim Hexal, or lenograstim, respectively, at a dose of 5 to 10 µg/kg body weight subcutaneously starting from Day 5 after chemomobilization with CAD (cyclophosphamide, doxorubicin, dexamethasone) until completion of PBSC collection. RESULTS: All but one patient reached the collection goal of a minimum of at least 2 × 106 CD34+ cells/kg body weight during a median of one (range, one to three) leukapheresis session. No significant differences in CD34+ mobilization and collection yields between the filgrastim-mobilized (median, 10.5; range, 2.7-40.4), Filgrastim Hexal-mobilized (median, 9.9; range, 0.2-26.0), and lenograstim-mobilized (median, 10.7; range, 3.1-27.9 CD34+ cells × 106 /kg body weight) patients were observed. CONCLUSION: Concerning the clinically relevant efficiencies of PBSC mobilization and in terms of reaching the individual collection target, this retrospective study did not detect any significant differences between the three G-CSF variants in the analyzed patient cohort.

The influence of rituximab-containing chemotherapy on HCV load in patients with HCV-associated non-Hodgkin's lymphomas.

Efficacy and safety of rituximab treatment in patients with Hepatitis C virus (HCV) infection associated non-Hodgkin's lymphoma (NHL) are still disputable. The aim of this study was to evaluate the influence of rituximab-containing chemotherapy on HCV load. Fifty-four patients with both HCV infection and NHL were identified between 2000 and 2016 at our institution. We retrospectively analyzed patients' demographic characteristics, treatment, and kinetics of HCV load before and after treatment with rituximab-containing chemotherapy. In the total group of 54 patients, 29 (54%) received rituximab. Both HCV load pre rituximab and maximal HCV load post rituximab were available in 16 patients. Overall, we observed no significant difference between HCV load pre rituximab and the maximal HCV load post rituximab (P = 0.19). In a patient who was treated simultaneously with direct-acting antivirals (DAAs) and rituximab-containing chemotherapy, HCV load decreased below the sensitivity level (≤12 IU/ml) during treatment. When regarding the influence of rituximab-containing chemotherapy alone on HCV load, we observed a significant elevation of HCV load (P = 0.04). Rituximab-containing chemotherapy may lead to an increase of HCV load in patients with HCV-associated NHL. However, this finding is based on small patient cohort and should be confirmed in larger clinical trials.

Comparison between intermittent and continuous spectra optia leukapheresis systems for autologous peripheral blood stem cell collection.

Terumo BCT recently introduced a new system for mononuclear cell (MNC) collection that uses a Spectra Optia apheresis machine equipped with a redesigned disposable kit and software program (version 11.2). It allows for the continuous collection of MNCs, unlike the original Spectra Optia system (version 7.2), which included a chamber for two-step cell separation. The aim of this study was to compare the two apheresis systems in regard to specific performance parameters. A retrospective data analysis of 150 patients who had undergone peripheral blood stem cell collection between March of 2014 and May of 2015 at our institution was performed. For the matched comparison, patients were divided into two groups by diagnosis and by previous forms of therapy received: a homogeneous group of patients with multiple myeloma (MM) that had received first line therapy ("MM" group, n = 88) and a heterogeneous group that included all of the other patients ("other" group, n = 62). No significant differences in CD34+ collection yields between both collection regimens were found (pMM = 0.19, pother = 0.74) in either group. Moreover, similar performance ratios (collected/predicted CD34+ cell number in %) were observed (pMM = 0.89, pother = 0.1). No relevant variations in platelet or hemoglobin loss were found between the two systems. We conclude that the new continuous Spectra Optia MNC system is equally efficient in collecting CD34+ cells and can be used without sacrificing collection efficiency levels when treating a broad variety of autologous patients. J. Clin. Apheresis 32:27-34, 2017. © 2016 Wiley Periodicals, Inc.