Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial.

The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.

Health status and infections in patients with symptomatic primary and secondary immunoglobulin G (IgG) deficiencies receiving intravenous IgG replacement.

BACKGROUND: The effects of intravenous immunoglobulin G replacement on perceived health and infection susceptibility of patients suffering from immunoglobulin G (IgG) deficiencies should be evaluated in a prospective analysis. METHODS: Patients with symptomatic primary or secondary IgG deficiencies were interviewed prior to the first IgG infusion (t0) and over the course of their treatment (t1 - t6). The respondents rated their current health using a 100 point scale (EQ-5D-5L), ranging from 0 ('worst imaginable health') to 100 ('best imaginable health'). The patients also provided information on the frequency of infections and of infections requiring antibiotics in the past 8 weeks. A healthy control group (CG) without oncologic diseases answered the questions once. RESULTS: One hundred six patients with a median age of 65 years (21-85 years) were investigated. The median serum IgG concentration changed from 500 mg/dl (t0) to 772 mg/dl (t6). The mean number of infections and of infections requiring antibiotics decreased during IgG replacement significantly. Current health according to EQ-5D-5L improved from 57 (t0) to 68 (t6), compared to 73 in the CG. CONCLUSION: During the course of IgG replacement patients reported fewer and less severe infections. Their health assessment improved but still was inferior to the healthy CG.

Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma.

BACKGROUND: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. METHODS: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. RESULTS: Since this is the publication of a study protocol of an ongoing study, no results can be presented. DISCUSSION: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. TRIAL REGISTRATION: NCT02495922 on June 24th, 2015.

High adherence of patients with multiple myeloma who receive treatment with immunomodulatory drugs (IMIDS) in hematology/oncology group practices in Germany.

PURPOSE: Immunomodulatory drugs (IMIDS) have changed the treatment and outcome of patients suffering from multiple myeloma. However, with the oral administration adherence becomes an issue. Since there is no "gold standard" in measuring adherence, we assessed the adherence of myeloma patients with the help of different data sources. METHODS: All patients who have been receiving IMIDS for at least 3 months were eligible. Computer assisted personal interviews of patients and, if possible, their caregivers were carried out. Attending oncologists evaluated the patient's adherence with the help of a standardized questionnaire. In addition, a retrospective analysis of prescription data was conducted. All data were analyzed statistically using SPSS. RESULTS: One hundred myeloma patients, 35% female, 65% male, with a median age of 70 years (37-86) were interviewed. Prescription data could be evaluated in terms of adherence in 78 patients (78%), 56 caregivers could be questioned (56%). Ninety-seven percent of patients rated themselves as adherent in taking IMIDS. Data from treating oncologists, caregivers and prescriptions supported this result. IMID therapies were rated as very effective and significant, toxicities were acceptable and dosing regimens simple/uncomplicated. CONCLUSIONS: Myeloma patients seem to be highly adherent to IMID treatments.

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.

Rituximab in combination with chemotherapy for the treatment of chronic lymphocytic leukaemia in clinical practice.

OBJECTIVES: This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. METHODS: Prospective, multicentre, observational study with rituximab-containing chemoimmunotherapy in CLL patients. RESULTS: Of 681 patients in total, 485 were enroled in cohort 1 (unselected) and 196 in cohort 2 (comorbid "slow-go" patients). The median patient age was higher than in most randomised controlled trials (cohort 1: 70 years and cohort 2: 75 years). The most common treatment regimen in both first-line and relapsed patients was rituximab-bendamustine. Two-year progression-free survival rate for first-line therapy was 84.1% for cohort 1 and 69.8% for cohort 2 (with best overall response rate 81.8% for cohort 1 and 76.6% for cohort 2). General and B-symptoms declined during treatment and remained at low level or decreased further until study end. The safety profile observed in randomised clinical trials was confirmed. CONCLUSION: Chemoimmunotherapy with rituximab is feasible and safe in a wide variety of clinical settings in CLL, including the treatment of older patients with comorbidities (ClinicalTrials.gov NCT01178086).

Management of patients with malignancies and secondary immunodeficiencies treated with immunoglobulins in clinical practice: Long-term data of the SIGNS study.

OBJECTIVE: We aimed to describe the current management and outcomes of patients with secondary immunodeficiencies (SID) on intravenous (IV) or subcutaneous (SC) immunoglobulins (IG) as maintenance therapy to prevent infections. METHODS: Non-interventional, prospective study (average follow-up 20.5 months). RESULTS: Of the 307 SID patients (mean age 63.7±14.4 years, 52% males, in 31% IG newly initiated), 95.4% received IV IG (mean dosing interval 4.6 weeks, average dose 199 mg/kg per 4 weeks) and 4.6% were treated with SC IG (2.6 weeks, 343 mg/kg per 4 weeks). Median IG through level at first documentation was 5.8 g/L and did not differ between IV and SC treatment or between underlying malignancies. In 24.1% of patients, treatment was interrupted temporarily, over a mean of 11.6±6.3 months. In patients with newly initiated IG treatment the 82% overall infection rate prior to treatment dropped to 21% at 1 year. CONCLUSIONS: Under clinical practice conditions, IG replacement therapy in SID patients was feasible, diminished infection rates and improved quality of life. Average IG doses were relatively low. Tolerability of IV IG treatment was excellent.

Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma. Results of the HD2002 prospective multicentre randomized phase III trial.

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m(2) every 3 months for 2 years) versus observation was evaluated for CD20(+) B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00-1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05-0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.

Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial.

The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.

Therapy of HIV-associated lymphoma-recommendations of the oncology working group of the German Study Group of Physicians in Private Practice Treating HIV-Infected Patients (DAGNÄ), in cooperation with the German AIDS Society (DAIG).

AIDS-related aggressive B cell lymphoma (HIV-NHL) is the second most common HIV-associated malignancy. In contrast, Hodgkin-lymphoma (HL) is one of the most common non-AIDS-defining malignancies. Current evidence-based recommendations for the treatment of HIV-associated lymphoma (HIV-lymphoma) are not available. A panel of experts in the field of HIV-related lymphoma performed literature searches of the PubMed, Medline, and Cochrane databases. The consensus process was carried out as an e-mail and meeting-based discussion group. Six cycles of R-CHOP or R-EPOCH are standard of care for patients (pts) with diffuse large B cell lymphoma (DLBCL). Pts with Burkitt lymphoma and good performance status should receive dose-intensive regimens such as the GMALL B-ALL/NHL protocol. Standard therapy has not been defined for pts with plasmablastic and primary effusion lymphoma. Pts with lymphoma in sensitive relapse should receive high-dose chemotherapy followed by autologous stem cell transplantation. Stage- and risk adapted treatment yields high remission and survival rates in pts with HIV-HL similar to those achieved in HIV-negative HL pts. Combination antiretroviral therapy (cART) should be applied concurrently to chemotherapy provided that pharmacokinetic interactions are being considered. Pts with HIV-lymphoma should usually be treated in an identical manner to HIV-negative patients.

Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial.

BACKGROUND: The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma. METHODS: GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18-70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0-3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1-2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, and on days 1 and 11 for cycles 3-4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1-28 for cycles 1-3; thereafter, up to 15 mg orally on days 1-28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1-6, and on day 1 for cycles 7-26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed. FINDINGS: Between June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7-55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61-77), 69% (61-76), 66% (58-74), and 67% (59-75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both. INTERPRETATION: Addition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma. FUNDING: Bristol Myers Squibb/Celgene and Chugai.

Treatment of neurological autoimmune diseases with immunoglobulins: first insights from the prospective SIGNS registry.

PURPOSE: Several immunoglobulin (IG) preparations have been approved for the immunomodulatory treatment of the neurological autoimmune diseases (AID) Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). Although efficacy has been proven in randomised clinical trials, long-term outcome data on drug utilization, effectiveness, tolerability, health related quality of life, and economic variables are lacking. METHODS: In the prospective, observational internet-based SIGNS registry, patients of all age groups are eligible if they have received or are scheduled for IG therapy for neurological AID or primary or severe secondary immunodeficiency. RESULTS: Of the 306 patients currently included in the database (1 November 2011), 51 have neurological AID (27 males; mean age 56 ± 15 years): 21 CIDP, 7 MMN, 11 multiple sclerosis (MS), 6 myasthenia gravis, 2 myositis, 4 others (no cases of GBS). Mean duration of disease since first symptoms was 7.8 years, and disease duration since diagnosis was 5.9 years. Eight different IG preparations have been reported as current therapy. According to SF-36, patients' quality of life is substantially impaired. CONCLUSIONS: Present data indicate some off-label use of IG (e.g. in MS) in patients with neurological AID. Quality of life in these patients is substantially compromised. Increasing patient numbers and extended follow-up periods will provide data on treatment concepts and disease development in AID patients.

HIV-associated lung cancer: survival in an unselected cohort.

BACKGROUND: Lung cancer is one of the most common non-AIDS-defining malignancies in HIV-infected patients. However, data on clinical outcome and prognostic factors are scarce. METHODS: This was a national German multicentre, retrospective cohort analysis of all cases of lung cancer seen in HIV-infected individuals from 2000 through 2010. Survival was analyzed with respect to the use of antiretroviral therapy (ART), specific lung cancer therapies, and other potential prognostic factors. RESULTS: A total of 72 patients (mean age 55.5 y, CD4 T-cells 383/µl) were evaluated in this analysis. At time of lung cancer diagnosis, 86% were on ART. Of these, 79% had undetectable HIV-1 RNA (< 50 copies/ml) for a mean duration of 4.0 y. All but 1 patient were current or former heavy smokers (mean 42 package y). The median estimated overall survival was 1.08 y, with a 2-y overall survival of 24%. The prognosis did not improve during the observation time. A limited lung cancer stage of I-IIIA was associated with better overall survival when compared with the advanced stages IIIb/IV (p = 0.0003). Other factors predictive of improved overall survival were better performance status, CD4 T-cells > 200/µl, and a non-intravenous drug use transmission risk for HIV. CONCLUSIONS: Currently, most cases of lung cancer occur in the setting of limited immune deficiency and a long-lasting viral suppression. As in HIV-negative cases, the clinical stage of lung cancer is highly predictive of survival, and long-term overall survival can only be achieved at the limited stages. The still high mortality underscores the importance of smoking cessation strategies in HIV-infected patients.

Treatment of limited stage follicular lymphoma with Rituximab immunotherapy and involved field radiotherapy in a prospective multicenter Phase II trial-MIR trial.

BACKGROUND: The optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy. METHODS/DESIGN: The MIR (Mabthera® and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combination's efficacy and safety with an accrual of 85 patients.Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life. DISCUSSION: The trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only). TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00509184.

Clinical outcome of patients with follicular lymphoma and bulky disease after rituximab-CHOP immunochemotherapy with and without consolidating radiotherapy.

BACKGROUND: The strategy to apply involved-field radiotherapy (IF-RT) after immunochemotherapy in patients with bulky follicular lymphoma (FL) remains controversial. PATIENTS AND METHODS: To evaluate the benefit of consolidating IF-RT, we retrospectively analysed relapse patterns and survival of patients with bulky FL. All patients were treated within a multicenter prospective randomized trial on 126 patients with one, three or six cycles Rituximab and six cycles CHOP. According to the protocol, patients presenting with bulky disease were to undergo consolidating IF-RT after immunochemotherapy. Forty-two eligible patients with bulky disease were identified, of which 26 were irradiated and 16 were not, contrary to the demand of the protocol. RESULTS: There was no significant difference between the irradiated and the non-irradiated group regarding presenting characteristics (P > 0.05). After a median follow-up of 60 months, 21 patients relapsed. In the irradiated group, relapse occurred in 12 of 26 patients. Fifty percent of relapses were located within the original bulk or within the bulk plus a new location. In the non-irradiated group, 9 of 16 patients relapsed. There was no statistically significant difference between exposure to IF-RT and the likelihood of a relapse per se (P = 0.751) or at a specific location (P = 0.66). Six-yr-PFS- (P = 1.0) and OS-rates (P = 0.68) were 52% and 80% after IF-RT and 48% and 73% without IF-RT. CONCLUSION: There was no difference in relapse rate, PFS and OS between patients treated with and without consolidating IF-RT. This is the first analysis of its kind conducted in the Rituximab era. However, these results are based on a relatively small cohort size and are derived from a retrospective analysis, with the limitations of such an analysis being well known.

Quality of life during maintenance therapy with the anti-CD20 antibody rituximab in patients with B cell non-Hodgkin's lymphoma: results of a prospective randomized controlled trial.

The introduction of rituximab into the primary treatment of malignant lymphomas of the B cell lineage has had a major impact on the management of these diseases. In addition, prolonged exposure to rituximab as maintenance therapy has been beneficial in patients with follicular lymphoma and mantle cell lymphoma. For the individual patient, the effect of any prolonged antitumor therapy on the quality of life (QoL) is a very important question. However, so far, the question whether rituximab maintenance therapy may impair QoL in patients with non-Hodgkin's lymphoma remains unanswered. To investigate this subject, we have performed a prospective randomized trial of rituximab maintenance therapy (8 cycles rituximab 375 mg/m(2) every 3 months) versus observation in patients with CD20+B cell non-Hodgkin's lymphoma in our institution. Between July 2002 and December 2005, 122 patients were included into the trial. QoL was assessed with the standardized questionnaires EORTC-QLQ-C30, EuroQol-5D, and EuroQol-5D (VAS) in 91 patients. After statistical analysis with the exact Wilcoxon rank sum test, we found no significant differences of the QoL between the rituximab treatment group and the observation group. We conclude that rituximab maintenance therapy seems to be safe and does not impair quality of life in this patient population.

Patients With Malignant Lymphoma and HIV Infection Experiencing Remission After First-Line Treatment Have an Excellent Prognosis.

BACKGROUND: Malignant lymphoma is still the leading cause of death among AIDS-related diseases. PATIENTS AND METHODS: We performed a retrospective analysis of 50 HIV-positive lymphoma patients. The median interval between HIV and malignant lymphoma diagnosis was 4 years. Eight patients (16%) had Hodgkin lymphoma and 42 (84%) non-Hodgkin lymphoma. Among non-Hodgkin lymphoma patients, diffuse large B-cell lymphoma (n = 18, 42%), Burkitt lymphoma (n = 11, 26%), and plasmoblastic lymphoma (n = 5, 12%) were the most frequent entities. RESULTS: Lymphoma was treated according to standard protocols. Forty-four patients (88%) received combination antiretroviral therapy, 2 (4%) were not treated, and in 4 (8%) the HIV treatment status was not clarified. Response to first-line therapy was complete response (CR) in 24 (56%), partial response (PR) in 15 (35%), and stable disease in 1 (2%). Three patients (7%) developed progressive disease, and 9 (18%) experienced relapse after CR or PR. At a median observation period of 31 (range, 0.4-192) months, the 1-, 2-, and 5-year overall survival was 87%, 79%, and 76%, respectively. At univariate analysis, remission status after first-line treatment was predictive of outcome, as the 2-year overall survival was 95%, 66%, and 0 for patients with CR, with PR, and with progressive disease (P < .001). Results of the multivariate analysis revealed lactate dehydrogenase concentration at lymphoma diagnosis (P = .046) and relapse (P = .050) to be independent factors for overall survival. CONCLUSION: First-line treatment of lymphoma in HIV positive patients is crucial. Patients who experienced and maintained a first CR had a favorable prognosis.

Drug-perturbation-based stratification of blood cancer.

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.