Kirit M Ardeshna

Rituximab versus a watch-and-wait approach in patients with advanced- stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial

BACKGROUNDnPatients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL).nnnMETHODSnAsymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931.nnnFINDINGSnBetween Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved.nnnINTERPRETATIONnRituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma.nnnFUNDINGnCancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

Guidelines for the first line management of classical Hodgkin lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients’ representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach.

18F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder

Abstract The aim of the present study was to investigate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the diagnosis of post-transplant lymphoproliferative disorder (PTLD), a serious complication of solid organ and bone marrow transplant. Between January 2004 and January 2012, 40 patients (22 males; median age 52 ± 17.4 years, range 11–77 years) underwent 18F-FDG PET/CT scans in our department for diagnostic evaluation of PTLD. Twenty-three (57.5%) patients had negative 18F-FDG PET/CT and 17 (42.5%) had a positive examination. In five patients PET/CT revealed extranodal disease (adrenal, pleural, spleen, liver, lung, esophagus and bone involvement). On the basis of our results, 18F-FDG PET/CT had a sensitivity of 88.2% (95% confidence interval [CI] 0.62–0.98), a specificity of 91.3% (CI 0.70–0.98), a positive predictive value of 88.2% (CI 0.62–0.98) and a negative predictive value of 91.3% (CI 0.70–0.98). The diagnostic performance of CT in patient-based analysis was: a sensitivity of 87.5% (CI 0.60–0.97), a specificity of 88.8% (CI 0.64-0.98), a positive predictive value of 87.5% (CI 0.60–0.97) and a negative predictive value of 88.8% (CI 0.64–0.98). PET/CT in five cases revealed more findings than CT, upstaging the disease, and revealed three extranodal findings, not visualized in conventional imaging. 18F-FDG PET/CT plays a significant role in the setting of PTLD diagnosis, demonstrating its high accuracy in detecting PTLD.

FLT PET-CT in evaluation of treatment response.

Purpose: Review published studies to investigate the value of clinical 3-deoxy-3-18F-fluorothymidine (FLT) positron emission tomography (PET) in predicting response to treatment. Materials and Methods: Interrogate databases to identify suitable publications between 2007 and 2013 with a minimum of five patients. Articles within the inclusion criteria were reviewed with major findings reported leading to a descriptive analysis of FLT PET in therapy response. Results: Lesions investigated included glioma, head and neck, esophageal, lung, breast, gastric, renal, rectal, sarcomas, germ cell, lymphomas, leukemia, and melanoma resulting in a total of 34 studies analyzed. A variety of therapies were applied and dissimilar PET protocols were widespread making direct comparison between studies challenging. Though baseline, early and late therapy scans were popular particularly in chemotherapy regimes. Most studies investigated showed significantly reduced FLT uptake during or after therapy compared with pretreatment scans. Conclusion: Current evidence suggests FLT PET has a positive role to play in predicting therapy response especially in brain, lung, and breast cancers where good correlation with Ki-67 is observed. However, careful attention must be placed in undertaking larger clinical trials where harmonization of scanning and analysis protocols are strictly adhered to fully assess the true potential of FLT PET in predicting response to treatment.

Hotel-based ambulatory care for complex cancer patients: a review of the University College London Hospital experience.

Abstract Since 2005, University College London Hospital (UCLH) has operated a hotel-based Ambulatory Care Unit (ACU) for hematology and oncology patients requiring intensive chemotherapy regimens and hematopoietic stem cell transplants. Between January 2005 and 2011 there were 1443 patient episodes, totaling 9126 patient days, with increasing use over the 6-year period. These were predominantly for hematological malignancy (82%) and sarcoma (17%). Median length of stay was 5 days (range 1–42), varying according to treatment. Clinical review and treatment was provided in the ACU, with patients staying in a local hotel at the hospitals expense. Admission to the inpatient ward was arranged as required, and there was close liaison with the inpatient team to preempt emergency admissions. Of the 523 unscheduled admissions, 87% occurred during working hours. An ACU/hotel-based treatment model can be safely used for a wide variety of cancers and treatments, expanding hospital treatment capacity, and freeing up inpatient beds for those patients requiring them.

Mini-BEAM is effective as a bridge to transplantation in patients with refractory or relapsed Hodgkin lymphoma who have failed to respond to previous lines of salvage chemotherapy but not in patients with salvage-refractory DLBCL

Patients with relapsed or refractory lymphoma can be cured with stem cell transplantation if they are shown to have disease that is responsive to salvage chemotherapy. Patients who fail to respond to first‐line salvage chemotherapy tend to do very poorly. Here we report on 39 such patients who received mini‐BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy as second or subsequent‐line salvage chemotherapy. Fifty‐six percent of these patients had primary refractory disease and a further 28% had responses to first‐line therapy that lasted <12 months. Seventy‐two percent had progressive disease following the salvage chemotherapy administered immediately prior to mini‐BEAM and the remaining 28% had stable disease. Overall there was a 38% response to mini‐BEAM (complete response = 28%, partial response = 10%). Patients with Hodgkin lymphoma (HL) had a higher response rate compared to those with diffuse large B cell lymphoma (DLBCL) (63% vs. 20%). Seventy‐four percent of HL patients were able to proceed to transplantation compared with 30% of patients with DLBCL. Mini‐BEAM is a very effective bridge to transplantation in very poor risk patients with HL who have failed to respond to first‐line salvage chemotherapy. Its efficacy in non‐Hodgkin lymphoma is more modest.

Autologous stem cell transplantation remains beneficial for patients relapsing after R‐CHOP chemotherapy and who respond to salvage chemotherapy

The initial results of the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study have recently been reported (Gisselbrecht et al, 2010). This study focused on the comparison of R-DHAP (dexamethasone, cytarabine, cisplatin, rituximab) versus R-ICE (ifosfamide, carboplatin, etoposide, rituximab) salvage chemotherapy in patients with diffuse large B cell lymphoma (DLBCL) in first relapse or refractory to firstline chemotherapy. Patients who achieved a complete (CR) or partial response (PR) went on to autologous stem cell transplantation (ASCT). The study confirmed that patients who had received prior rituximab did worse, after failure of first line therapy, with a 3-year event-free survivial of 21% compared with 47% in patients who had not been exposed to rituximab previously. Whilst it was clear that patients who received prior rituximab responded less well to the rituximabcontaining salvage chemotherapy when compared with those who had not received prior rituximab (51% vs. 83%) the impact of prior rituximab amongst the subjects who responded to salvage chemotherapy and proceeded to ASCT was not explored. We were interested to see if patients with relapsed/ refractory DLBCL who responded to salvage chemotherapy and proceeded to ASCT had a poorer outcome following ASCT if they had received rituximab with their induction CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy when compared with patients who received CHOP alone. If this were the case, alternative investigational strategies, such as reduced-intensity allogeneic transplantation, may be worthy of exploration in this group of patients. We undertook a retrospective analysis of patients aged 18 years or older who received high dose therapy using BEAM (carmustine 300 mg/m d-6, etoposide 200 mg/m d-5 to d-2, cytarabine 200 mg/m bd d-5 to d-2, melphalan 140 mg/m d-1) chemotherapy followed by ASCT for relapsed/refractory DLBCL in our unit since 1994. We limited our analysis to patients who received CHOP with or without rituximab as first-line therapy and who also required no more than two different lines of salvage chemotherapy to demonstrate chemo-sensitivity prior to transplant. Ten of 115 (9%) transplanted patients were excluded from the analysis because of incomplete information about their pre-transplant status and treatment received. Response to treatment was assessed by computerized tomography (CT) in the earlier cohort of patients with positron emission tomography (PET)-CT being used more recently. International Working Group criteria for reporting were used (Cheson et al, 1999, 2007). Progression-free survival (PFS) and overall survival (OS) was estimated using the Kaplan Meier method and outcomes compared using the log-rank method. A P value of <0Æ05 was considered significant. PFS was defined as time from date of stem cell return to date of disease progression or death. OS was defined as time from date of stem cell return to death. Patient characteristics were compared using Fisher’s exact test (2-sided) for standard 2 · 2 comparisons, and the Mann Whitney test (2-sided) for age and time from diagnosis to transplant. Of the 105 patients were identified, 72 had received CHOP as first-line therapy and 33 had received R-CHOP. Of the 72 CHOP patients, 14 (19%) subsequently received rituximab during salvage treatment. Patient characteristics are detailed in Table I. There were significantly more males in the CHOP group. Additionally, there was a trend towards lower age and a greater number of lines of salvage therapy in the CHOP group. The groups were balanced for the number of inductionrefractory cases (35/72 vs. 16/33, P = 1Æ00) and the number of patients relapsing late (>12 months from first line chemotherapy) (18/72 vs. 5/33, P = 0Æ32). All patients demonstrated chemosensitivity prior to ASCT, with responses post-salvage chemotherapy being 32% CR (n = 23) and 68% PR (n = 49) in the CHOP group and 36% CR (n = 12) and 64% PR (n = 21) in the R-CHOP group (P = 0Æ66). Best response following ASCT was determined in 85% of patients in both the CHOP and R-CHOP patients. Of the 61 evaluable CHOP patients, 51 (84%) had achieved a CR, 2 (3%) a PR, 2 (3%) SD and 6 (10%) had progressive disease. In the 28 evaluable R-CHOP patients, 22 (79%) had achieved a CR, 4 (14%) a PR, and 2 (7%) had progressive disease. The median follow up for the CHOP group was 5Æ68 years (0Æ11–17Æ0 years) and 3Æ38 years for the R-CHOP group (0Æ25–7Æ66 years). The 5-year OS and PFS following ASCT was 64% and 50% respectively in the CHOP group, compared to 69% and 62% in the R-CHOP group (P = 0Æ64 and P = 0Æ29 respectively). This was confirmed when the analysis included only patients with refractory disease or those relapsing <12 months after diagnosis (Fig 1). In those 15% of patients in whom a best response was not ascertained, there was no difference in survival between the CHOP and R-CHOP groups. Correspondence

Treatment of diffuse large B-cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS-penetrating R-IDARAM chemotherapy.

Diffuse large B‐cell lymphoma with secondary involvement of the central nervous system (SCNS‐DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS‐DLBCL treated with R‐IDARAM (rituximab 375 mg/m2 IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m2/day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1–3; cytosine arabinoside 1000 mg/m2/day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m2 IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation (‘new disease’), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded ‐ 6 (26%) complete response, 8 (35%) partial response. Grade 3–4 haematological toxicity was seen in all cycles, with no grade 3–4 or long‐term neurological toxicity. Median follow‐up for surviving patients was 49 months. At 2 years, estimated progression‐free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5‐year estimated PFS of 50% and OS 75%. R‐IDARAM is a well‐tolerated regimen with encouraging efficacy in patients with SCNS‐DLBCL, although patients with relapsed or refractory disease continue to fare poorly.

CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial

Summary Background Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. Methods We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0–3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1–5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1–5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). Findings Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6–38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21–1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. Interpretation The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. Funding Bloodwise and the UK National Institute of Health Research.

Cardiac tamponade in Hodgkin lymphoma

A 33-year-old woman was receiving her second cycle of combination chemotherapy (etoposide, methylprednisolone, cytarabine, cisplatin; ESHAP) for relapsed Hodgkin lymphoma when she complained of worsening dyspnoea. Until this point she had been well, her relapsed disease having been detected on a follow-up computerised tomography (CT) scan. The patient had not received radiotherapy as part of her initial treatment. At presentation she was tachycardic (110 bpm) and hypotensive (blood pressure 90/55 mm Hg). The jugular venous pressure was elevated at 10 cm above the sternal angle and rose on inspiration. Auscultation revealed quiet heart sounds. Her chest radiograph (top left) showed a large globular cardiac silhouette an enlarged mediastinal node. She was not hypoxic; an urgent CT pulmonary angiogram showed no evidence of pulmonary embolism but a large global pericardial effusion (top right). An echocardiogram showed preserved myocardial function but significant compromise of diastolic filling. A pericardial drain was inserted and 1Æ5 l of fluid were collected. Cytology confirmed the presence of large mononuclear Hodgkin cells and Reed-Sternberg cells, which were CD30 positive (bottom panels). Although pleural effusions are common in patients with lymphoma, pericardial effusions are rare. We could find only one previous report of a patient with Hodgkin lymphoma suffering a massive pericardial effusion (Gabrys et al, 1997). Our patient received second-line salvage chemotherapy (carmustine, etoposide, cytarabine, melphalan; miniBEAM) and an allogeneic stem cell transplant. She is currently in remission and making good progress 4 months after her allograft. The effusion has not recurred.