Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001). INTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. FUNDING: F Hoffmann-La Roche.

Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party.

The aim of this project was to define indications for hematopoietic stem cell transplantation in follicular lymphoma in Europe. In the absence of evidence-based data, a RAND-modified Delphi procedure was used by an expert panel. After pre-defining statements, these were individually/anonymously scored by each participant using a 9-point scale. Consensus was reached that: 1) high-dose therapy with autologous stem cell rescue is not an appropriate option to consolidate first remission in patients responding to immuno-chemotherapy outside clinical trials; 2) in patients with first chemo-sensitive relapse, high-dose therapy with autologous stem cell rescue is an appropriate option to consolidate remission, especially in patients with a short response after immuno-chemotherapy or with high-risk FLIPI; 3) high-dose therapy with autologous stem cell rescue is also appropriate in second/subsequent chemo-sensitive relapses; 4) allotransplant (preferably a reduced intensity conditioning-allotransplant) should be considered at relapse after high-dose therapy with autologous stem cell rescue. No consensus was reached on the role of high-dose therapy with autologous stem cell rescue in low-risk first relapse, or on when an allotransplant should be preferred over high-dose therapy with autologous stem cell rescue. In the absence of evidence-based data, the consensus method used was a valuable tool to define indications for hematopoietic stem cell transplant in follicular lymphoma.

Risk Factors for and Outcomes of Follicular Lymphoma Histological Transformation at First Progression in the GALLIUM Study.

BACKGROUND: Although advanced­stage follicular lymphoma (FL) is considered incurable, survival has improved with the introduction of the anti-CD20 antibodies, rituximab (R) and obinutuzumab (G). However, FL can undergo histological transformation (HT) to a more aggressive disease, and a validated model for predicting HT risk is not yet available. PATIENTS AND METHODS: We assessed HT incidence, risk factors and outcomes in the phase III, GALLIUM study evaluating R- or G-chemotherapy in patients with previously untreated, advanced-stage FL (ClinicalTrials.gov NCT01332968). HT rates were assessed by repeat tumour biopsy at disease progression or relapse, at the investigator's discretion. RESULTS: Of 1202 patients enrolled, 315 (26.2%) experienced progressive disease; 46 (14.6%) had a biopsy at first progression, 40 of whom had biopsy-confirmed HT. HT risk factors were male sex (subdistribution hazard ratio [sHR], 2.21; 95% confidence interval [CI], 1.16-4.20), elevated baseline serum lactate dehydrogenase (sHR, 3.97; 95% CI, 2.03-7.76), and elevated baseline serum ß2-microglobulin (sHR, 1.96; 95% CI, 1.02-3.79). Patients with HT at first progression had poorer post-progression survival than those with relapsed FL (2-year rate: 55.9% vs. 83.1%). Relapse with HT occurred earlier than FL relapse (median time from randomisation: 0.8 vs. 2.3 years). CONCLUSION: HT was a low-frequency event associated with poor survival outcomes in the GALLIUM study. Male sex and elevated baseline levels of serum LDH and B2M were significant risk factors for HT. Further research is required to develop validated prognostic indices for HT risk and guide treatment decisions.

Haematopoietic stem cell transplantation does not retard disease progression in the psycho-cognitive variant of late-onset metachromatic leukodystrophy.

Haematopoietic stem cell transplantation has an unproven role in the management of late-onset metachromatic leukodystrophy: theoretically justified through the engraftment of enzyme-replete haematopoietic progenitors and restoration of capacity for sulphatide catabolism in neural tissue through enzyme recapture, the long-term outcome is unknown. The rarity of the psycho-cognitive variant and slow progression of late-onset disease impairs evaluation of treatment. We report detailed clinical and neuropsychological assessments after haematopoietic stem-cell transplantation in a patient with a late-onset psycho-cognitive form of metachromatic leukodystrophy. Cognitive decline, indistinguishable from the natural course of the disease, was serially documented over 11 years despite complete donor chimaerism and correction of leukocyte arylsulphatase A to wild type values; subtle motor deterioration was similarly noted and progressive cerebral volume loss was evident upon magnetic resonance imaging. Sensory nerve conduction deteriorated 17 months post-transplantation with apparent stabilisation at 11-year review. Haematopoietic stem-cell transplantation was ineffective for this rare attenuated variant of metachromatic leukodystrophy. In the few patients identified pre-symptomatically or with early-phase disease, clear recommendations are lacking; when transplantation is considered, umbilical cord blood grafts from enzyme-replete donors with adjunctive mesenchymal stem cell infusions from the same source may be preferable. Improved outcomes will depend on enhanced awareness and early diagnosis of the disease, so that promising interventions such as genetically modified, autologous stem cell transplantation have the best opportunity of success.

Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety.

Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m2 on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.

Anthracycline-based chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation.

BACKGROUND: Recommended first-line treatment for posttransplant lymphoproliferative disorder (PTLD) is reduction in immunosuppressive therapy, irrespective of histopathological type. Second-line treatment with chemotherapy is generally reserved for tumors that fail to respond to reduced immunosuppression. In view of the similarities between monomorphic PTLD and non-Hodgkin's lymphoma in the general population, our policy is to treat monomorphic PTLD with anthracycline-based chemotherapy as first-line treatment. METHODS: A retrospective single-center analysis of 18 adults who developed PTLD following liver or kidney transplantation was undertaken, with particular emphasis on tumor histology, treatment received, and clinical outcome. RESULTS: Of the 18 patients with PTLD, 13 had high-grade malignant lymphoma on diagnostic biopsy and received anthracycline-based chemotherapy and reduction in immunosuppression as first-line therapy. Nine (69%) of the 13 patients achieved complete remission and eight (62%) remained in complete remission five years after diagnosis. There was no graft loss from rejection or drug toxicity. Four (22%) patients had polymorphic PTLD on diagnostic biopsy (of which two were re-classified as monomorphic) and one had a low-grade malignant lymphoma. All five patients were treated by reduction in immunosuppression without chemotherapy and were in complete remission at a median of two years after diagnosis. Overall, complete remission was seen in 14 out of 18 patients (78%) at one year following diagnosis. CONCLUSION: The use of anthracycline-based chemotherapy and reduction of immunosuppression as first-line treatment in adults with monomorphic PTLD is well tolerated and achieves sustained complete remission in around 70% of patients with a low risk of graft loss.

Follicular lymphoma: time for a re-think?

Follicular lymphoma (FL) is a malignancy of follicle centre B cells that have at least a partially follicular pattern, and is the commonest type of indolent Non-Hodgkin's lymphoma. Except in the subset of patients with localized disease, FL should still be regarded as an incurable malignancy with a relentless relapsing/remitting course. However, the provocative new data covered by this review (including anti-CD20 antibody therapy, BCL-2, radioimmunotherapy, new chemotherapeutic agents and anti-idiotype vaccination), provides much cause for excitement and guarded optimism. Rituximab represents a novel treatment approach for a variety of disease settings, with a proven excellent efficacy and toxicity profile. Long-term data is required to establish whether its use translates into survival benefit. As the clinical activity of rituximab and other new therapeutic approaches becomes established, it will be important to determine how best to integrate these results into the standard care of patients with follicular lymphoma.

Autoimmune hemolytic anemia: magnetic resonance findings.

Idiopathic autoimmune hemolytic anemia (AIHA) is a rare hematological disease typically characterized by extracellular hemolysis. An unusual case of AIHA with interesting magnetic resonance imaging (MRI) appearances is presented. Possible explanations for the MRI findings are discussed.

HIV status does not impair the outcome of patients diagnosed with diffuse large B-cell lymphoma treated with R-CHOP in the cART era.

OBJECTIVE: To compare the outcome of patients diagnosed with HIV infection and diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP in the cART era with that of a HIV-negative control group. METHODS: From 2003 to 2011, 305 patients (97 HIV-positive) were diagnosed with DLBCL and treated with R-CHOP. Clinical features were compared using chi-square or Fisher's exact test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed using the Cox regression proportional hazards model. RESULTS: HIV-positive patients had more B symptoms and extranodal sites of disease at diagnosis, but the proportion of patients with high-intermediate/high-risk disease according to the international prognostic index (IPI) was similar between groups. Response rate was 73%, both for patients with and without HIV infection. After a median follow-up of 48 months, 30 patients relapsed after achieving a complete remission, including four HIV-positive patients. Ninety-six patients have died (19 HIV-positive), 73 of them due to DLBCL. Three patients (one HIV-positive) died due to treatment toxicity. Patients with HIV infection had a significantly longer disease-free survival (DFS) (5-year: 94 vs. 77%; P = 0.03) and overall survival (OS) (78 and 64% for HIV-positive and HIV-negative patients, respectively; P = 0.03). These results were confirmed on multivariate analysis when controlled for other potential prognostic confounders. CONCLUSION: HIV-positive patients diagnosed with DLBCL in the cART era have an excellent outcome when treated with standard immunochemotherapy. Therefore, the choice of chemotherapy in patients with lymphoma should not be influenced by HIV status.

Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study.

PURPOSE: In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years. PATIENTS AND METHODS: Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m(2) intravenously once every 3 months) or observation. RESULTS: Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01). CONCLUSION: With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.

BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study.

PURPOSE: The prognostic value of residual BCL2/immunoglobulin heavy chain (BCL2/IgH) -positive cells in peripheral blood (PB) or bone marrow (BM) after induction treatment in follicular lymphoma (FL) is still controversial. In a prospective randomized phase III intergroup trial of 465 patients with relapsed/resistant follicular lymphoma (FL), we showed that addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone induction results in increased overall and complete response rates, and that rituximab maintenance strongly improves median progression-free survival (PFS) as well as overall survival. Here, we studied whether BCL2/IgH major break point levels in PB/BM correlated with response rates/quality for the induction phase and PFS for the maintenance phase. PATIENTS AND METHODS: Samples were obtained before and after induction therapy and at the end of the 2 years maintenance/observation period. BCL2/IgH major break point-positive cells were quantified by genomic quantitative polymerase chain reaction in 792 samples from 238 patients. RESULTS: Pretreatment BCL2/IgH levels had no significant prognostic value for overall response or complete remission rates after induction treatment, but pretreatment positive BM results had an adverse prognostic value for PFS from first randomization (P = .023). Importantly, BCL2/IgH levels at the end of induction treatment had no prognostic value for PFS from second randomization. The highly significant improved PFS by rituximab maintenance was observed in both BCL2/IgH PB/BM-positive and -negative groups. CONCLUSION: Postinduction BCL2/IgH major break point status in BM/PB is not useful for decisions on subsequent therapy for patients with relapsed/resistant FL.

Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial.

We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m(2) intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m(2) intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.

Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation.

To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.

Significant and persistent loss of bone mineral density in the femoral neck after haematopoietic stem cell transplantation: long-term follow-up of a prospective study.

Reduced bone mineral density (BMD) has been reported following allogeneic stem cell transplantation (alloSCT) but the effects of autologous SCT (autoSCT) are less well characterized. We performed a prospective study of BMD changes and its determinants in 44 SCT recipients (38 auto and six allo; 30 peripheral blood SCT and 14 bone marrow transplantation). Serial measurements of BMD at the lumbar spine and femoral neck were performed at baseline and at 3, 6, 12 and 24 months, and spinal radiographs were performed at baseline and 12 months. Mean baseline BMD values at the femoral neck and spine were within normal limits. At 3 months, there was a significant decline of BMD at the femoral neck (P = 0.011) and a non-significant trend towards reduction at the spine. BMD loss persisted for up to 2 years at the femoral neck (P = 0.005), but values returned to baseline at the spine. Reflecting the rapid initial decline in BMD, bone-specific alkaline phosphatase (a serum marker of bone formation) showed a significant initial decline at 1 month but had recovered to pretransplant levels by 3 months. No new fractures were detected at 1 year post transplant. Sex, diagnosis, use of total body irradiation, stem cell source and type of graft (auto versus allo) did not significantly predict BMD change over the first 12 months. In conclusion, significant and persistent bone loss at the femoral neck was demonstrated in this group of patients following stem cell transplantation. The implications of these findings for future fracture risk require further study.