Adult T-cell leukemia/lymphoma (ATLL) is a mature (post-thymic) T-cell lymphoma associated with human T-lymphotropic virus type 1 infection. Survival in aggressive subtypes remains poor, and treatment resistance is frequent. Use of zidovudine (ZDV) and interferon alfa (IFN-α) has been associated with improved response rates in small studies and prolonged overall survival in leukemic ATLL subtypes in a recent meta-analysis.We report the clinicopathologic characteristics, treatment, and outcome of 73 patients with aggressive ATLL (acute ATLL, 29; lymphoma ATLL, 44) diagnosed and treated in England between 1999 and 2009. The impact of ZDV/IFN-α on treatment response and survival was assessed.The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). Median overall survival (OS) was 9 months: 7.5 months for acute ATLL and 10 months for lymphoma ATLL. Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL (hazard ratio, 0.23; 95% CI, 0.09 to 0.60; P = .002). Combined first-line therapy prolonged median OS in acute (P = .0081) and lymphoma ATLL (P = .001) compared with chemotherapy alone.These data support the use of low-dose ZDV/IFN-α with chemotherapy in first-line treatment of acute and lymphoma ATLL.
Introduction: CNS dissemination is an uncommon event in PMLBCL. International cooperation is an important tool to improve our knowledge on this poorly-investigated condition. Methods: Data from PMLBCL pts with CNS disease at presentation or relapse treated at 24 Centers from 6 countries were analyzed. Results: 41 pts (median age 32, range 14-52; 22 males) were considered. At initial lymphoma diagnosis, 20 (49%) had advanced stage, 21 (51%) B symptoms, 39 (95%) bulky disease, 37 (90%) raised LDH, 18 (44%) had extranodal disease (16 in abdomen), 26 (63%) had an aaIPI ≥2. First-line treatment was CHOP14/21 in 20 pts, daEPOCH in 6, M/VACOP-B in 15, combined with rituximab in 39 (95%), and followed by mediastinal irradiation in 14. CNS prophylaxis was administered in 6 pts. CNS involvement was recorded at initial diagnosis in one (2%) pt, at first relapse in 34 (83%), at 3rd-4th relapse in 6 (15%), with a median time to CNS relapse of 7 (0-24) months. CNS was the only site of recurrence in 24 (59%) pts, all at first relapse. Brain or cerebellum were involved in 38 (93%) pts, associated with meningeal infiltration in 6 of them, spinal cord in 1; meninges were the exclusive site of disease in 2 (5%) pts. Treatment was followed by complete remission in 13 pts (32%; 95%CI = 18-46), all of them were treated at presentation or first relapse, and, with a single exception, received high-dose-methotrexate (HD-MTX)-based therapy plus ASCT ± WBRT (Table). Twenty-four treated pts experienced further tumor failure, invariably in the CNS, with concomitant systemic disease in 8; 10 pts with progressive disease limited to the CNS received WBRT, combined with ASCT and/or other drugs, 8 achieving a CR lasting 16-84 months (Table). Pts with CNS involvement at 3rd-4threlapse also had systemic, uncontrolled disease, and did not benefit from treatment. At a median follow-up of 61 (10-173) months, 9 pts remain relapse-free, with a 5-yr PFS after CNS relapse of 21±6%, and 17 pts are alive, with a 5-yr survival after CNS relapse of 42±8%. Systemic disease and meningeal infiltration were not associated with outcome. The 5-yr survival after CNS relapse of the 26 pts treated with HD-MTX-based combinations was 52±10%. Conclusions: Advanced stage, abdominal extranodal disease and high LDH levels are often recorded in PMLBCL pts with CNS recurrence. Unlike other aggressive lymphomas, CNS involvement at presentation and meningeal infiltration are rare in PMLBCL. Prognosis is poor, but HD-MTX-based therapy and consolidative ASCT are associated with encouraging results. WBRT contributes to the achievement of long-lasting remission even in pts with chemorefractory disease. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Lymphoid Cancers - Other No conflicts of interest pertinent to the abstract.
Although most lymphoma subtypes have been reported in the eye, [1] the vast majority of ocular lymphomas are non-Hodgkin lymphomas (NHLs) of B-cell type; a small minority (1%–2%) are derived from T-lymphocytes or natural killer cells. [1] Here, we report a rare case of conjunctival peripheral T-cell lymphoma not otherwise specified (PTCL NOS) in a 47-year-old female. Slit-lamp examination showed salmon-colored limbal thickening of the conjunctiva, characteristic of conjunctival lymphoma. This was associated with bone marrow and lymph node involvement. The lymphoma was treated with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy, followed by consolidation with autologous hematopoietic stem cell transplantation, resulting in durable complete systemic and conjunctival remission at 6 months of follow-up. Conjunctival T-cell lymphoma can present with minimal and nonspecific symptoms, making it imperative for the clinician to consider ocular lymphoma when presented with unexplained conjunctivitis.
A 57-year-old man was diagnosed with stage IV CD4+ CD56+ haematodermic neoplasm (plasmacytoid dendritic cell precursor neoplasm) in June 2007. This rare and aggressive malignancy involved his skin, lymph nodes and bone marrow, but not his cerebrospinal fluid (CSF), at presentation. He was treated with two alternating courses of CODOX-M (cyclophosphamide, vincristine, doxorubicin, cytarabine and methotrexate) and IVAC (ifosfamide, etoposide and cytarabine) chemotherapy, with intrathecal methotrexate and cytarabine prophylaxis, to complete remission in September 2007. In November 2007, he complained of blurred vision in his right eye and was subsequently diagnosed with a unilateral central retinal vein occlusion (figure), which dramatically reduced his vision to ‘counting fingers’. A computed tomography scan of his head and orbits was normal and the patient refused CSF examination. Treatment with 50 mg of cyclophosphamide and 20 mg of prednisolone daily was commenced with the aim of preventing the left eye being similarly affected. Biopsy of a new chest rash later that month confirmed relapse. By January 2008 his right visual acuity had improved to 6/60 (Snellen chart) but he was also discovered to have a haemorrhagic conjunctival lesion of his left eye. A diagnostic excision biopsy was performed as this was his only eye with good vision (6/9). On haematoxylin and eosin staining this showed cells with hyperchromic and pleomorphic nuclei. These neoplastic cells stained positive for CD4+ and CD56+. Retinal vein occlusion has not previously been reported to be associated with haematodermic neoplasm. The timing of this event as a harbinger of systemic disease relapse, and its blindingly obvious symptomatology, makes it a valuable clinical alarm bell.
Introduction: Diffuse large B cell lymphoma (DLBCL) is a clinically heterogeneous disease. Increasing emphasis is being placed on the prognostic impact of tumour biology to identify groups at highest risk of treatment failure. Chromosomal rearrangements enhancing the activity of the MYC proto-oncogene (MYCr) have been linked to adverse outcomes although some studies suggest that cases harbouring additional translocations affecting BCL2, BCL6 or both, have the worst outcomes. There is currently no consensus on the management of MYCr, ‘double-hit’ (DH) and ‘triple-hit’ (TH) cases. Retrospective data suggests that whilst treatment intensification is associated with an improved PFS, it does not translate to an improved overall survival (OS). Moreover recent evidence suggests that the MYC translocation partner may be important in prognostication. We aimed to capture the trends in current management of patients with these high risk alterations in a pan-London retrospective study. Methods: DLBCL patients with MYCr, DH or TH were identified at 9 London centres. Demographics, cytogenetics, treatment and outcomes were obtained from patient records and anonymised data was submitted for analysis. OS was defined as survival from date of diagnosis until death, censored at last follow-up. Median OS and follow-up time were calculated using the Kaplan Meier (KM) and reverse KM method respectively. Log-rank test was used to assess differences in median OS. Results: 101 patients (pts) have been evaluated to date. MYC rearrangement was the sole abnormality in 51 cases. 34 had DH (22 with BCL2 and 12 BCL6 rearrangement) and 16 TH. Median age was 65 yrs (Range 18-93). IPI was evaluable in 95 cases (0-2 in 28 and 3-5 in 67 pts). There was no significant difference in median age or IPI comparing sole MYCr cases to DH/ TH cases. Of the 101 pts, 27 (17 MYCr, 10 DH/TH) received either R-CODOX M/ R-IVAC or DA R-EPOCH. A further 53 pts received R-CHOP or similar regimens with an equal split between MYCr and DH/TH cases. The remaining had alternative treatments and a minority received only palliation. With a median follow-up of 25 months, the median OS for pts with MYCr was not reached (NR) versus 15 months for pts with DH/ TH, p= 0.2 (Figure 1a). In pts under 70 years, median OS for pts with DH/ TH (n=36) was 13 months versus NR in the MYCr pts (n=33), p=0.02 (Figure 1b). In these younger pts with DH/ TH OS was 13 months in pts who received R-CHOP like chemotherapy (n= 23) and 15 months in those who had R-CODOX M/ R-IVAC or DA R-EPOCH (n=10). Conclusions: Patients with DH/TH lymphomas in our cohort had a dismal outcome irrespective of age and IPI emphasizing the need for newer treatment strategies. The data shows a trend towards better outcome in patients with sole MYCr compared to those with DH/TH. This difference is striking in patients under 70, with a significantly better outcome in favour of those with sole MYCr. Data collection is ongoing to investigate the outcomes according to MYC translocation partner. Keywords: “double-hit” lymphomas; MYC.
Rituximab, a chimeric murine-human anti-CD20 antibody, is one of the most widely used biological agents in the treatment of lymphoma (Oldham & Dillman, 2008). Infusion-related reactions (IRR) to rituximab occur in around 80% of patients receiving their first dose (Schwartzberg et al, 2008, https://www.gene.com/download/pdf/rituxan_prescribing.pdf). Severe IRRs to rituximab are less common, with 7% of patients experiencing Common Terminology Criteria for Adverse Events (CTCAE) grade 3–4 reactions (Schwartzberg et al, 2008). However, patients who suffer severe IRRs to rituximab often fail re-challenge (Levin et al, 2017). Patients intolerant of rituximab due to IRRs are likely to have a worse outcome in terms of progression-free survival and overall survival if they are precluded from further anti-CD20 therapy. Ofatumumab, a fully humanised anti-CD20 monoclonal antibody, has so far been shown to have a favourable safety profile and may therefore represent a viable alternative. Around 60% of all adverse events to ofatumumab are IRRs (Coiffier et al, 2008). The overall rate of IRRs to first exposure of ofatumumab has been shown to be around 40%, with the majority of IRRs being grade 1–2 reactions that do not preclude further treatment (Wierda et al, 2011; Korycka-Wołowiec et al, 2015). Few studies have investigated the rate of ofatumumab IRRs in patients who are intolerant of rituximab due to grade 3–4 IRRs. Therefore, our aim was to ascertain the feasibility of using ofatumumab as an alternative anti-CD20 therapy in rituximab-intolerant patients by: (i) investigating the rate and severity of ofatumumab IRRs, and (ii) assessing the practicalities of administering ofatumumab in this group with regard to infusion times and need for inpatient admission. Thirteen patients were identified who had been treated at University College London Hospital between 2011 and 2016, who were intolerant of rituximab due to grade 3–4 IRRs and had been given ofatumumab as an alternative. A total of 64 ofatumumab infusions were administered to these 13 patients. Median number of infusions per patient was 4 (range 2–13). Clinical notes and infusion charts were available for 39 of these infusions. Ofatumumab infusion data was divided according to cycle number: 1st cycle (300 mg test dose), 2nd cycle (1000 mg) and 3rd cycle onwards (1000 mg). Infusion data were missing for one 1st cycle infusion, four 2nd cycle infusions and 20 3rd cycle onwards infusions. All patients received steroids and histamine H1 receptor antagonists prior to ofatumumab administration. Data regarding the severity and nature of reaction to rituximab and ofatumumab were ascertained from clinical records. IRR severity was classified according to the National Cancer Institute CTCAE version 3.0 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf). The median age of the patients was 57 years (range 30–83 years); 62% of the patients were female and 38% male. The majority of patients (77%) were Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and the remaining patients had an ECOG status of 2–3. All patients were receiving anti-CD20 therapy for lymphoma. Of the 13 patients who had previous severe IRRs to rituximab, treatment had been discontinued in 12, due to CTCAE grade 4 reactions, and in 1 patient due to CTCAE grade 3 reactions (Table 1). The grade 4 reactions were all anaphylactoid; the grade 3 reaction was persistent fever. The median number of exposures to rituximab before switching to ofatumumab was 2 (range 1–4). 2 (hypotension): 1st 1 (rash): 3rd Only 6 of the 13 patients had any IRR to ofatumumab. Of the 39 ofatumumab infusions studied, 8 caused an IRR. All of the IRRs to ofatumumab were CTCAE grade 1–2 with no CTCAE grade 3–4 IRRs (Table 1). All 39 ofatumumab infusions were completed; no infusions were discontinued due to IRRs. Out of the 8 IRRs, 6 occurred during the 1st dose of ofatumumab, 1 occurred during the 2nd dose and 1 during 3rd dose onwards. All patients who reacted to ofatumumab were able to continue with subsequent ofatumumab infusions, with only 2 patients reacting a second time. Median ofatumumab infusion times were 8·7 h (range, 7·6–18·3 h), 6·1 h (range, 5–16 h) and 4 h (range 4–8·2 h) for the 1st, 2nd and 3rd onwards doses of ofatumumab, respectively (see Fig 1). All patients, except one, were able to increment the rate of infusion with subsequent cycles. Compared to the minimum licensed ofatumumab infusion times for the 1st, 2nd and 3rd onwards doses of 6 h, 6 h and 4 h respectively, the median infusion time for 1st dose ofatumumab was longer in our group. Of the 39 ofatumumab infusions studied, 11 were started as inpatient infusions and 28 were started in the outpatient setting. The most common reason for admitting patients for infusions was to monitor for signs of reaction during first exposure to ofatumumab; 7 of the 11 inpatient ofatumumab infusions were 1st cycle infusions admitted for this reason. Of the 28 infusions started in outpatients, 6 required admission: half of the admissions were due to IRRs and the other half were related to long infusion times. Later cycles of ofatumumab were mostly administered in outpatients; with 74% (14/19) of 3rd cycle onwards infusions being administered entirely in the outpatient setting. Overall, all patients intolerant of rituximab due to severe IRRs in our study were able to tolerate ofatumumab treatment. The majority of ofatumumab infusions in these patients did not cause any IRR. All of the IRRs to ofatumumab were mild CTCAE grade 1–2 reactions that did not preclude further ofatumumab administration. Infusion times of early ofatumumab cycles were longer in rituximab-intolerant patients than minimum licensed infusion times and a small proportion of infusions started in the outpatient setting required admission for this reason. Most admissions for ofatumumab infusions were pre-planned 1st cycle infusions. The majority of later cycles (3rd cycle onwards) of ofatumumab were fully administered in the outpatient setting. Limitations of our study include a small sample size, incomplete infusion data and retrospective data collection. In conclusion, our study suggests that ofatumumab is a feasible alternative anti-CD20 therapy in patients intolerant of rituximab. Our data shows a similar safety profile of ofatumumab to other studies (Coiffier et al, 2010; Wierda et al, 2011; Korycka-Wołowiec et al, 2015). Continuing anti-CD20 therapy in rituximab-intolerant patients is likely to be of clinical benefit, however further studies are needed to assess the efficacy and safety of ofatumumab compared to rituximab. LYC collected the data and wrote the paper. RS and LYC analysed the data. KMA designed the study. KMA, KC, JL, CM, SGM, AV, WT, RS, SD provided the data and edited the paper. KMA is supported by UCL/UCLH Biomedical Research Centre. The authors have no competing interests.
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