Claire Hemmaway

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial

BACKGROUND Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article. METHODS For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920. FINDINGS Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity. INTERPRETATION With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials. FUNDING Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia

The development of new treatments for older patients with acute myeloid leukaemia (AML) is an active area, but has met with limited success. Sapacitabine is a novel orally administered nucleoside analogue that has shown encouraging activity in unrandomised early-stage trials. We randomised 143 untreated patients with AML or with high-risk myelodysplastic syndrome (>10% marrow blasts) between sapacitibine and low-dose ara-C (LDAC) in our ‘Pick a Winner’ trial design. At the planned interim analysis there was no difference between LDAC and sapacitibine in terms of remission rate (CR/CRi, 27% vs 16% hazard ratio (HR) 1.98(0.90–4.39) P=0.09), relapse-free survival (10% vs 14% at 2 years, HR 0.73(0.33–1.61) P=0.4) or overall survival (OS; 12% vs 11% at 2 years, HR 1.24(0.86–1.78) P=0.2). Sapacitibine was well tolerated, apart from more grade 3/4 diarrhoea. On the basis of these findings sapacitibine did not show sufficient evidence of benefit over LDAC for the trial to be continued.

Cervical carotid artery disease in sickle cell anemia: clinical and radiological features

Cervical internal carotid artery (cICA) occlusion is a recognized cause of acute ischemic stroke (AIS) in sickle cell disease (SCD), but the associated clinical and radiologic features are not well described. We reviewed data on cervical magnetic resonance angiography (cMRA) performed prospectively in 67 patients (55 children) for indications including transcranial Doppler (TCD) abnormalities, AIS, or previous AIS. cICA lesions were seen in 10 (15%) patients, including 4 of 7 patients presenting with AIS, and appear to have been missed on first presentation in 4 of 10 patients with previous AIS. Radiologic features in 7 patients were consistent with dissection. In 2 patients, there was strong clinical and radiologic evidence for thromboembolic AIS, and this was also considered possible in 4 other patients. Three of the 4 AIS patients were anticoagulated acutely, and the nontreated patient had recurrent, probably thromboembolic, AIS. TCD findings were variable, but in 4 patients there were high velocities in the cerebral vessels contralateral to the cICA stenosis. We suggest that all patients with AIS should have cMRA during acute evaluation to identify cICA occlusions that may require anticoagulation. Routine screening of children with SCD should also include evaluation of neck vessels by carotid Doppler followed by cMRA if a cervical vascular lesion is suspected.

Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial

BACKGROUND The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy. METHODS HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2 on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m2 on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920. FINDINGS Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT. INTERPRETATION WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision. FUNDING Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

Catastrophic thrombosis in idiopathic hypereosinophilic syndrome

A 43-year-old female was admitted with shortness of breath, chest pain and digital ischaemia. On examination she was hypotensive, tachycardiac and tachypnoeic and had a tender epigastrium and swollen tender left lower leg. A full blood count showed a white cell count of 21 2 9 10/l with 22% eosinophils (absolute eosinophil count 4 6 9 10/l) and a platelet count of 14 9 10/l. Liver function tests were abnormal with an alkaline phosphatase of 393 iu/l, alanine transaminase of 498 iu/l and a lactate dehydrogenase level of 2497 iu/l. D-dimer and troponin T were markedly elevated at 26 630/l and 7 26 lg/l, respectively. Clotting studies, including a Clauss fibrinogen, were normal apart from a prolonged prothrombin time of 17 s. The blood film was leucoerythroblastic with a marked eosinophilia. Eosinophil morphology was normal. A Doppler ultrasound of the lower limbs demonstrated bilateral deep vein thromboses from the superficial femoral vein to the tibial veins. Computed tomography (CT) pulmonary angiography showed bilateral extensive pulmonary emboli with a saddle embolus in the main pulmonary artery (left). A CT scan of the abdomen and pelvis demonstrated a thrombus in the suprahepatic inferior vena cava (right, white arrow) extending into the right atrium and across the tricuspid valve. Hepatomegaly with right hepatic and portal vein occlusion with thrombus (right, black arrows) were also noted. A full work up for parasitic, malignant and rheumatological diseases was negative. JAK2 V617F, BCR-ABL1 and FIP1L1-PDGFRA were negative by polymerase chain reaction. There was no evidence of a Bor T-cell clone by peripheral blood Band T-cell receptor rearrangement analysis. A full thrombophilia screen was negative. Bone marrow aspirate and trephine biopsy sections were hypercellular with a marked eosinophilia. There was no increase in mast cells. Cytogenetic analysis and flow cytometry on the bone marrow aspirate were normal. Platelet transfusions were given and the patient was commenced on an unfractionated heparin infusion. She was then transferred to the nearest cardiothoracic unit where she underwent inferior vena cava filter insertion and thrombolysis. She was commenced on prednisolone 1 mg/kg per d for 2 weeks, which was then tapered over the next 8 weeks. The patient was successfully warfarinized and remains thrombusfree, on anticoagulation, 3 years later. Her full blood count and liver function tests are normal apart from an eosinophil count of 0 5 9 10/l. She has not required retreatment with prednisolone. This case illustrates multiple life-threatening simultaneous thromboses in association with hypereosinophilic syndrome (HES) and disseminated intravascular coagulation. Physicians should be aware of the thromboembolic complications of HES. About 25% of patients develop thromboembolism and 5–10% die as a result. The underlying mechanism of thrombosis is not fully understood but at least four granule proteins released by eosinophils are thought to cause hypercoagulability.

FDG‐PET guided diagnosis of vaginal intravascular diffuse large B‐cell lymphoma

A 76-year-old woman presented with a 6-month history of progressive bilateral lower limb weakness, anorexia and weight loss and the recent onset of urinary and faecal incontinence with saddle anaesthesia. There was no palpable lymphadenopathy. Urgent magnetic resonance imaging (MRI) ruled out spinal cord or cauda equina compressive lesions. Blood tests showed a raised lactate dehydrogenase (LDH) and erythrocyte sedimentation rate with an IgM paraprotein of 7 g/l; immunoglobulins were otherwise normal. Cerebrospinal fluid analysis showed a reactive lymphocytosis on morphology and by flow cytometry. Bilateral bone marrow aspirates and trephine biopsies were normal. Computed tomography (CT) was entirely normal but a repeat MRI with gadolinium showed enhancement of lumbosacral nerve roots suggestive of infiltrative disease. [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) showed diffuse uptake in the uterus, cervix, vagina and numerous groups of lymph nodes throughout the body. The FDG-PET findings led to a vaginal mucosal biopsy, which showed subepithelial capillaries packed with neoplastic lymphoid cells (left) expressing CD20 (right), CD79a and CD5 with a Ki-67 index of 100%; the histological features were those of intravascular diffuse large B-cell lymphoma (DLBCL). At the time of diagnosis the patient had a performance score of 4 and she remained an inpatient. She received twice weekly intrathecal methotrexate, followed by one cycle of CVP (cyclophosphamide, vincristine and prednisolone combination chemotherapy). Rituximab was given 1 week later due to the high risk of tumour lysis syndrome, which has been reported previously. Unfortunately she developed neutropenic sepsis and died 2 weeks after diagnosis. Despite extensive prior investigations it was the results of the FDG-PET scan that eventually guided the biopsy site. The lack of solid lesions makes routine CT and MRI unhelpful in diagnosing this rare subtype of extranodal DLBCL; approximately 50% of patients are diagnosed at autopsy. This case highlights how the nonspecific and diverse symptoms, in the absence of significant lymphadenopathy, can result in critical delays in diagnosing this clinically aggressive lymphoma and how the use of FDG-PET scanning in such patients can guide the biopsy site.

Deferasirox for iron chelation in multitransfused children with sickle cell disease; long-term experience in the East London clinical haemoglobinopathy network.

Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long‐term efficacy and safety in children.

Irreversible blindness secondary to posterior reversible encephalopathy syndrome following CHOP combination chemotherapy

A 60-year-old woman, diagnosed with stage 3B peripheral T-cell lymphoma, unclassified, commenced CHOP combination chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone). She complained of blurred vision bilaterally following cycle 3 and visited her local optometrist, who found no ocular abnormalities. She continued CHOP chemotherapy but the blurred vision progressed. After cycle 5 she was seen in the Ophthalmology department, where no abnormality was detected on intraocular examination but visual acuity was reduced. Ten days following cycle 8, the patient’s vision deteriorated dramatically, to light perception only and the family reported mild fluctuating confusion. Magnetic resonance imaging (MRI) of the brain showed bilateral high intensity lesions, mainly of the left occipital white matter on T2 weighted images and low intensity lesions on T1 weighted images, (images) consistent with advanced posterior reversible encephalopathy syndrome (PRES). Cerebrospinal fluid analysis showed normal protein and glucose concentrations, no malignant cells and negative polymerase chain reactions for cytomegalovirus and BK and JC viruses. A full autoimmune screen and HIV-1 and -2 serology were negative. PRES is a disorder associated with malignant hypertension (but the blood pressure can be normal or only mildly raised), renal disease, eclampsia and the use of immunosuppressive drugs, typically in haemopoietic malignancies. The cause is poorly understood, but is thought to be related to changes in cerebrovascular autoregulatory control. Features include headache, confusion, seizures and visual disturbance. Focal areas of symmetrical hemispheric oedema are typically seen on brain imaging, most commonly affecting the parietal and occipital lobes. The oedema usually reverses completely within days to weeks of removal of the trigger and control of the blood pressure, but permanent neurological disability can occur. This case highlights the difficulty in making the diagnosis in a normotensive patient whose initial complaint was of blurred vision only. The marked visual deterioration and confusion occurred after she had completed her treatment, whereas most cases of PRES in patients receiving CHOP chemotherapy have presented earlier, usually following the first course of chemotherapy. The patient did not exhibit other typical features of PRES, such as headaches or seizures. One year later there has been no improvement in her vision and she is registered blind. A previously reported case of post-CHOP PRES also showed no reversibility; however that patient died only 9 d following presentation with a tonic clonic seizure. (Cain et al, 1998). Clinicians should be aware that any visual symptoms in patients receiving CHOP chemotherapy should be closely monitored, and the patient should be assessed for the presence of headaches, confusion or seizures. Early investigation with an MRI scan of the brain should be done if symptoms do not resolve.

Cerebellar Cladophialophora bantiana infection in a patient with marginal zone lymphoma treated with immunochemotherapy including rituximab

A 60-year-old man with marginal zone lymphoma presented with a cerebellar syndrome comprising ataxia and horizontal nystagmus. He had completed his sixth cycle of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone) chemoimmunotherapy. A T1 weighted sagittal magnetic resonance image of the brain (left) showed a multilocular cystic mass in the posterior fossa, arising from the vermis, with associated oedema. A cystic glioblastoma was initially suspected. However excision and drainage of the lesion revealed necrosis with multinucleate giant cells and abundant pigmented fungal hyphae on microscopy and Gram stain (right). These were identified by the fungal reference laboratory as Cladophialophora bantiana, a dematiaceous soil-based fungus. Rituximab, a chimeric monoclonal antibody against the CD20 antigen on B cells, can significantly increase the risk of infections as a result of by B lymphocyte depletion. There are several reports of Pneumocystis jiroveci infection after its use. Rare infections, such as polyomavirus JC, leading to progressive multifocal leucoencephalopathy, and enterovirus meningoencephalitis have also been described. Cladophialophora bantiana is a highly neurotropic fungus. It usually disseminates to the brain through the bloodstream or lymphatics. Distribution of the fungus is worldwide, but infections are very rare and occur mainly in subtropical, nonarid climate zones; just over 70 cases have been published. Infections have been reported in solid-organ transplant patients, immune disorders, malignant disease, patients on corticosteroid therapy and immunocompetent healthy individuals. The patient was treated with a combination of voriconazole, flucytosine and amphotericin B on expert advice. Follow-up brain scans showed no recurrence of the cystic lesion in the cerebellum, but unfortunately the patient died following a prolonged period in the Intensive Care Unit with anti-fungal nephrotoxicity, sepsis and then a fatal intraventricular haemorrhage. The overall survival rate in patients with C. bantiana infection ranges between 28% and 35%. Mortality can be as high as 100% without treatment. Rituximab in combination with chemotherapeutic agents is an efficacious regimen for B-cell lymphomas. However its use can increase the risk of infections. A high index of suspicion for opportunistic infections should be maintained, as early diagnosis and treatment can improve patient outcome.

Transcranial Doppler Screening in a Regional Care Network for Sickle Cell Disease in the United Kingdom.

The risk of stroke in children screened with transcranial Doppler ultrasound in the United Kingdom is not known. We evaluated a clinician-led program using a risk assessment modified from the STOP protocol. High-risk classification included abnormal velocities in the anterior cerebral artery, and single abnormal scan if initial velocity >220 cm/s (high abnormal) or if preceded by at least 2 conditional scans. In total, 1653 scans were performed in 542 children, followed for 2235 patient-years. Fifty-eight (10.7%) high-risk subjects were identified, including 18 (31%) with high abnormal, and 15 (26%) with previous conditional scans. In 2 (3%), abnormal velocity was restricted to the anterior cerebral artery. The estimated proportion of children at high risk, scanned before 6 years of age was >20%. There were 4 cases of acute ischemic stroke (AIS) and 2 of acute hemorrhagic stroke. The incidence of all stroke, AIS, and acute hemorrhagic stroke were 0.27, 0.18, and 0.09 per 100 patient-years, respectively. The proportion of children at high risk is higher than most previous estimates, partly as a result of our modified risk assessment. About 2 children per 1000 screened with transcranial Doppler ultrasound progress to AIS.