Malignancy‐associated haemophagocytic lymphohistiocytosis in children and adolescents

Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M‐HLH) in 21 patients, most of whom had T‐ (n = 12) or B‐cell neoplasms (n = 7), with Epstein–Barr virus as a co‐trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch‐HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M‐ and Ch‐HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M‐HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch‐HLH patients had evidence of active HLH. To overcome HLH, malignancy‐ and HLH‐directed treatments were administered in the M‐HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch‐HLH, treatment ranged from postponement of chemotherapy to the use of etoposide‐containing regimens.     

Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation

This study investigated the efficacy of a pre‐emptive strategy based on the combination of Epstein–Barr virus (EBV) viraemia and poor T cell reconstitution in preventing post‐transplant lymphoproliferative disease (PTLD) following T cell depleted stem cell transplant (SCT). EBV viral load and immune reconstitution were prospectively monitored in 70 consecutive children undergoing SCT following reduced intensity conditioning with alemtuzumab. Patients who developed significant EBV viraemia (>40 000 copies/ml blood) were treated pre‐emptively with rituximab if they were within 3 months of SCT or their CD3 count was <0·3 × 10⁹/l. Of 20/70 patients who developed significant EBV viraemia, 13 received pre‐emptive rituximab. The incidence of PTLD was significantly reduced in the pre‐emptive cohort compared to historical controls (1·4% vs. 21·7%, P = 0·003). This difference was more marked among viraemic patients (2·7% vs. 62·5%P < 0·0001). Patients treated with rituximab demonstrated significantly delayed B cell reconstitution at 1 year post‐SCT but this was not associated with an increase in infectious mortality. In 6/6 patients >3 months post‐SCT who had a CD3 count >0·3 × 10⁹/l, reduced immunosuppression only resulted in successful resolution of EBV viraemia without PTLD. This strategy is safe and highly effective in preventing PTLD following T cell depleted SCT, and directs rituximab therapy to patients at highest risk of this complication.     

Front‐line,dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis

‘Double‐hit lymphomas’ (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard‐risk, diffuse large B‐cell lymphomas (DLBCL). Consequently, dose‐intensive (DI) therapies and/or consolidation with high‐dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta‐analysis compared survival outcomes in DHL patients receiving dose‐escalated regimens [DI: R‐Hyper‐CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R‐CODOX‐M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate‐dose: R‐EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard‐dose regimens (R‐CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first‐line setting. Data were synthesized to estimate hazard ratios of dose‐escalated treatments versus R‐CHOP using a Weibull proportional hazards model within a Bayesian meta‐analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front‐line R‐CHOP (n = 180), R‐EPOCH (n = 91), or R‐Hyper‐CVAD/rituximab, methotrexate, cytarabine (R‐M/C), R‐CODOX‐M/R‐IVAC (DI) (n = 123). Our meta‐analysis revealed that median progression‐free survival (n = 350) for the R‐CHOP, R‐EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First‐line treatment with R‐EPOCH significantly reduced the risk of a progression compared with R‐CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.     

Rituximab plus hyper‐CVAD alternating with MTX/Ara‐C in patients with newly diagnosed mantle cell lymphoma: 15‐year follow‐up of a phase II study from the MD Anderson Cancer Center

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long‐term follow‐up results for patients treated with these regimens. We present long‐term survival outcomes from a pivotal phase II trial of rituximab, hyper‐fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R‐HCVAD/MA) . At 15 years of follow‐up (median: 13·4 years), the median failure‐free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15‐year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10‐year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5–12·2%). In patients with newly diagnosed MCL, R‐HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one‐third of the younger patients (≤65 years).     

Treatment of rare co‐occurrence of Epstein–Barr virus‐driven post‐transplant lymphoproliferative disorder and hemophagocytic lymphohistiocytosis after allogeneic stem cell transplantation

In both conditions, post‐transplant lymphoproliferative disorder (PTLD) and hemophagocytic lymphohistiocytosis (HLH), infection with Epstein–Barr virus (EBV) is a key mechanism: almost all PTLD in allogeneic stem cell transplantation (alloSCT) is caused by EBV‐related neoplastic lymphoproliferation, and secondary HLH is most frequently triggered by EBV infection. Therefore, concomitant EBV‐driven PTLD and HLH early after alloSCT require an approach to eliminate EBV and balance immune activation simultaneously. We report on a patient who developed simultaneous PTLD and signs of HLH on day 64 after alloSCT. Treatment was comprised of stopping cyclosporine, short‐course dexamethasone, and 3 courses of rituximab. The patient showed full recovery and complete remission of lymphadenopathy. This result indicates that immediate reduction in EBV‐carrying B cells by rituximab, suppression of general inflammation, and parallel support of reconstitution of long‐term T‐cell function, might be an appropriate therapeutic approach in this rare situation.     

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m² pixantrone dimaleate (equivalent to 50 mg/m² in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.     

Iron‐chelating therapy with deferasirox in transfusion‐dependent,higher risk myelodysplastic syndromes: a retrospective,multicentre study

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR‐MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion‐dependent, intermediate‐to‐very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty‐six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375–2500 mg) for a median of 11 months (range 0·4–75). Eight patients (16%) showed grade 2–3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR‐MDS are comparable, in terms of safety and efficacy, with those observed in lower‐risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR‐MDS patients.     

Prospective phase II study of rituximab with alternating cycles of hyper‐CVAD and high‐dose methotrexate with cytarabine for young patients with high‐risk diffuse large B‐cell lymphoma

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R‐HCVAD) alternating with rituximab, high‐dose methotrexate, and cytarabine (R‐MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) in diffuse large B‐cell lymphoma (DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age‐adjusted international prognostic index ≥2 to R‐HCVAD/R‐MA or R‐CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate (CRR) was higher with R‐HCVAD/R‐MA than R‐CHOP (P = 0·03); thus, R‐CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R‐HCVAD/R‐MA and R‐CHOP arms respectively; CRR were 82% and 60% respectively (P = 0·13); 3‐year progression‐free survival (PFS) rates were 75·7% and 77·8% respectively (P = 0·53). In the R‐HCVAD/R‐MA arm, 3‐year PFS rates in patients aged 46–60 years and ≤45 years were 70·3% and 87·1% respectively (P = 0·13), and the treatment‐associated early mortality rate in patients >45 years was 12%. In conclusion, R‐HCVAD/R‐MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R‐HCVAD/R‐MA is associated with unacceptable mortality rates.     

A phase 1/2 trial of ublituximab,a novel anti‐CD20 monoclonal antibody,in patients with B‐cell non‐Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti‐tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti‐CD 20 monoclonal antibody, in rituximab‐relapsed or ‐refractory patients with B‐cell non‐Hodgkin lymphoma (B‐NHL ) or chronic lymphocytic leukaemia (CLL ). Induction therapy (doses of 450–1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL . Patients received ublituximab maintenance monthly during cycles 3–5, then once every 3 months for up to 2 years. Enrolled patients with B‐NHL (n  = 27) and CLL (n  = 8) had a median of 3 prior therapies. No dose‐limiting toxicities or unexpected adverse events (AE s) occurred. The most common AE s were infusion‐related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AE s were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n  = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression‐free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well‐tolerated and efficacious in a heterogeneous and highly rituximab‐pre‐treated patient population.     

A randomized phase II study of standard‐dose versus high‐dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B‐cell non‐hodgkin lymphomas: long term results

High‐dose rituximab (HD‐R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single‐arm prospective study of relapsed aggressive B‐cell non‐Hodgkin lymphoma (R‐NHL). We performed a randomized phase 2 study comparing HD‐R versus standard‐dose rituximab (SD‐R) in R‐NHL. Ninety‐three patients were randomized to HD‐R (1000 mg/m²) (n = 42) or SD‐R (375 mg/m²) (n = 51) administered on post‐transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow‐up of 7·92 years, the 5‐year disease‐free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD‐R and SD‐R in 5‐year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08–2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13–3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5‐year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B‐cell NHL, HD‐R provided no DFS or OS advantage over SD‐R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri‐transplant setting remains controversial.     

Rituximab extended schedule or retreatment trial for low tumour burden non‐follicular indolent B‐cell non‐Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub‐study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B‐cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31–49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.     

Impact of treatment variability on survival in immuno‐competent and immuno‐compromised patients with primary central nervous lymphoma

Patients with primary central nervous system lymphoma (PCNSL) treated in the ‘real‐world’ setting do not represent those treated on clinical trials and might not be treated similarly. We studied characteristics and variability in care for 113 newly diagnosed PCNSL patients treated at 5 institutions in the Chicago area between 2000 and 2012. In 111 patients, single modality therapy with a high dose methotrexate (HD‐MTX) regimen +/− rituximab, was most commonly employed (n = 65), and 34 underwent radiotherapy (+/− systemic therapy). Fifty‐eight of 108 patients received rituximab. Twenty‐nine of 110 patients (26%) received intrathecal chemotherapy (ITC). Overall response rate was 80% (47% complete responses). With a median follow‐up of 18·7 months, median overall survival (OS) was 65·2 months. In univariate analysis, HD‐MTX (median OS 72·7 vs. 2·7 months, P < 0·001) and rituximab (median not reached versus 28·4 months, P = 0·005) impacted OS favourably. This significance was sustained regardless of immune status and in multivariate analysis. Whole brain radiotherapy (WBRT) resulted in a trend for improved OS as compared with systemic therapy alone (P = 0·09), while ITC did not impact survival. Clinical practice has evolved to exclude WBRT and ITC while incorporating rituximab with clinical outcomes comparable in immuno‐competent/compromised patients and similar to those achieved in recent clinical trials.     

A multi‐centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m² weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty‐four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24/34) with 26·5% (9/34) achieving a complete response (CR). The time to response was 1 month post‐initiation of rituximab in 87·5% (21/24) and 3 months in 12·5% (3/24) of patients. The median duration of follow‐up was 36 months (range 6–90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6–60 months). Three patients were re‐treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re‐treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long‐term response.     

First‐line use of rituximab correlates with increased overall survival in late post‐transplant lymphoproliferative disorders: retrospective,single‐centre study

This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single‐centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29–69), median time to diagnosis 50 months (range 0–100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B‐cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non‐rituximab; P = 0.5). R‐CHOP‐like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31–96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58–79 months; non‐rituximab 1–30 months). Post‐transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single‐centre series, and it should be considered as first‐line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.     

Lenalidomide in combination with R‐ESHAP in patients with relapsed or refractory diffuse large B‐cell lymphoma: a phase 1b study from GELTAMO group

Diffuse large B‐cell lymphoma (DLBCL) patients failing rituximab‐containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose (MTD) of lenalidomide in combination with R‐ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) (LR‐ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1–14 of every 21‐day cycle, in combination with R‐ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem‐cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose‐limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR‐ESHAP cycles resolved appropriately and no grade 4–5 non‐haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow‐up of 24·6 (17·4–38·2) months, the 2‐year progression‐free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR‐ESHAP regimen is feasible and yields encouraging outcomes.     

Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T‐cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH. The average age was 53 years (range 18–77 years) and 43 were male (63%). Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%). Patients were treated with disease‐specific therapy and immunomodulatory agents. After a median follow‐up of 32·2 months, 46 patients had died (69%). The median overall survival was 4 months (95% CI: 0·0–10·2 months). Patients with malignancy had a worse prognosis compared to those without (median survival 2·8 months versus 10·7 months, P = 0·007). HLH is a devastating disorder with a high mortality. Further research is needed to improve treatment and outcomes.     

Changes in Serum Bicarbonate Levels Caused by Acetate‐Containing Bicarbonate‐Buffered Hemodialysis Solution: An Observational Prospective Cohort Study

Fresenius Medical Care's NaturaLyte dialysate has been associated with increased risk of sudden cardiac death by causing metabolic alkalosis from its acetate content based on retrospective data using pre‐dialysis bicarbonate levels only. The study objective was to measure inter/intra‐dialytic changes in serum bicarbonate and degree of alkalosis conferred by varying concentrations of NaturaLyte bicarbonate dialysate. Thirty‐nine hemodialysis patients were divided into four groups based on prescribed bicarbonate dialysate concentrations; Group 1 (N = 9): 30–32 mEq/L, Group 2 (N = 5): 33–34 mEq/L, Group 3 (N = 10): 35–36 mEq/L, Group 4 (N = 15): 37–40 mEq/L. Serial (pre‐dialysis, immediate post‐dialysis, 2 h post‐dialysis, and 68 h post‐dialysis) bicarbonate levels were measured. Mean pre‐dialysis serum bicarbonate levels (representing 44 h post‐dialysis levels) in all four groups were not statistically different. Pre‐dialysis and 68 h post‐dialysis bicarbonate levels in each group were also not significantly different. However, immediate post‐dialysis and 2 h post‐dialysis bicarbonate levels were significantly increased in all four groups proportional to dialysate dose. There was statistically significant inter‐group bicarbonate level difference (P < 0.05) except between the first and second (P = 0.43) and second and third (P = 0.07) groups in the immediate post‐dialysis period. Similar results were obtained for the 2 h post‐dialysis period. High bicarbonate dialysate causes large and rapid fluctuations in serum bicarbonate levels during the intra/inter‐dialytic period, which returns to baseline within 44 to 68 h after dialysis. This refutes the necessity to correct pre‐dialysis acidosis with high bicarbonate dialysate since rapid equilibration is likely to occur and unnecessarily exposes patients to large shifts in their acid base balance.     

A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia

This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre‐, mid‐ and post‐ each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19–130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment‐related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.     

A longitudinal evaluation of health‐related quality of life in patients with AL amyloidosis: associations with health outcomes over time

Light chain (AL) amyloidosis is a rare disease associated with significant, irreversible organ dysfunction and high case fatality. An observational study was conducted to assess health‐related quality of life (HRQoL) in patients treated for AL amyloidosis between 1994 and 2014 with both high dose melphalan and stem cell transplantation (HDM/SCT) or non‐SCT chemotherapy regimens. The SF‐36v1^® Health Survey (SF‐36) was administered to assess HRQoL during clinic visits. Analysis of variance was used to compare pre‐ and post‐treatment HRQoL within each treatment group to an age‐ and gender‐adjusted general population (GP) normative sample. Cox proportional hazard models were fit to examine associations between pre‐treatment levels of HRQoL and mortality within 1 and 5 years after initiating specific treatment regimens (HDM/SCT: n = 402; non‐SCT chemotherapy regimens: n = 172). Among patients who received HDM/SCT, there were significant improvements following treatment in vitality, social functioning, role‐emotional and mental health. Worse pre‐treatment SF‐36 physical component scores were associated with a greater risk of mortality in both treatment groups and follow‐up periods (P ≤ 0·005 for both). [Correction added on 20 October 2017, after first online publication: This P value has been corrected]. Using HRQoL assessments in every physician visit or treatment may provide valuable insights for treating rare conditions like AL amyloidosis.     

Clinical utility of next‐generation sequencing‐based minimal residual disease in paediatric B‐cell acute lymphoblastic leukaemia

We assessed the clinical utility of next‐generation sequencing (NGS)‐based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B‐cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre‐ (4–5 months) and post‐ (24 months) maintenance therapy time points, and at relapse. We identified leukaemia‐specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4–5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561–21·6), P < 0·001], at 4–5 months [RR (95% CI) = 10·24 (3·374–31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974–74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia‐free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS‐MRD for patients with B‐cell ALL.