Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard‐risk acute lymphoblastic leukaemia in first complete remission

We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard‐risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)‐matched sibling donor (MSD) and HLA‐matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II–IV acute graft‐versus‐host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III–IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5‐year cumulative transplant‐related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5‐year relapse rate post‐transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5‐year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5‐year disease‐free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3‐year GVHD‐free, relapse‐free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard‐risk adults with ALL in CR1 who lack matched donors.     

Pre‐transplant comorbidity burden and post‐transplant chronic graft‐versus‐host disease

The Haematopoietic Cell Transplantation‐Comorbidity Index (HCT‐CI) was designed as a predictor of non‐relapse mortality after HCT. Chronic graft‐versus‐host disease (GVHD) contributes to mortality after HCT. Here, we investigated whether the HCT‐CI could predict development of chronic GVHD or post‐chronic GVHD mortality. We retrospectively analysed data from 2909 patients treated with allogeneic HCT for malignant and non‐malignant haematological conditions at four institutions. In Cox regression models adjusted for potential confounders, increasing HCT‐CI was not statistically significantly associated with the development of chronic GVHD [hazard ratio (HR) = 1·02, P = 0·34]. Yet, the index was associated with an increased risk of non‐relapse mortality (HR = 1·29, P < 0·0001) as well as overall mortality (HR = 1·25, P < 0·001) following the development of chronic GVHD. The association between HCT‐CI and post‐chronic GVHD mortality was similar regardless of donor type or stem cell source. HCT‐CI scores could be incorporated in the design of clinical trials for treatment of chronic GVHD.     

Sequential chemotherapy followed by reduced‐intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT

This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML ) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced‐intensity conditioning (RIC ) and allogeneic haematopoietic stem cell transplantation (HSCT ). The transplants in 77 patients were from matched sibling donors (MSD s) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti‐T‐cell antibodies. The incidence of acute graft‐versus‐host disease (GVHD ) of grades II ‒IV was 32·1% and that of chronic GVHD was 30·2%. The 3‐year probability of non‐relapse mortality (NRM ) was 25·9%, that of relapse was 48·5%, that of GVHD ‐free and relapse‐free survival (GRFS ) was 17·8% and that of leukaemia‐free survival (LFS ) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II ‒IV [hazard ratio (HR ) = 1·98, P  = 0·017] and suffered less relapses (HR  = 0·62, P  = 0·01) than MSD recipients. Treatment with anti‐T‐cell antibodies reduced NRM (HR  = 0·35, P  = 0·01) and improved survival (HR  = 0·49, P  = 0·01), GRFS (HR  = 0·37, P  = 0·0004) and LFS (HR  = 0·46, P  = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti‐T‐cell antibodies seems promising in patients with refractory AML .     

Improved survival after offspring donor transplant compared with older aged-matched siblings for older leukaemia patients

Donor selection for older leukaemia patients undergoing haematopoietic cell transplant (HCT) is not well defined: outcomes might be improved with a younger offspring donor rather than an older human leukocyte antigen (HLA)-matched sibling donor (MSD). We extended our multicentre dataset. A total of 185 acute leukaemia patients (≥ 50 years) transplanted in first complete remission who received HCT from offspring (n = 62) or MSD (n = 123) were included. A 1:1 ratio matched-pair analysis was performed. We were able to match 54 offspring with 54 MSD patients. Outcomes were compared between the two matched-pair groups. The cumulative incidence of grade II/IV acute graft-versus-host disease (GVHD) (26% vs. 35%; P = 0·23) and chronic GVHD (37% vs. 24%; P = 0·19) was comparable between groups (MSD vs. offspring). The lower three-year transplant-related mortality (9% vs. 26%; P = 0·023) and relapse incidence (6% vs. 17%; P = 0·066) resulted in higher overall survival (85% vs. 58%; P = 0·003) and leukaemia-free survival (LFS) (85% vs. 56%; P = 0·001) in offspring HCT compared with that in MSD HCT. These data might favour a young offspring over an older MSD in patients >50 years. The current analyses confirm that non-HLA donor characteristics, such as kinship and donor age, rather than HLA disparity, predominantly influence survival in older acute leukaemia patients.     

Phase 2 study of tabalumab,a human anti‐B‐cell activating factor antibody,with bortezomib and dexamethasone in patients with previously treated multiple myeloma

In this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N  = 72), tabalumab 100 mg (N  = 74), or tabalumab 300 mg (N  = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m² on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS ]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR ) [95% confidence interval (CI )] = 1·13 [0·80–1·59], P  =  0·480; tabalumab 300 mg vs. placebo HR [95% CI ] = 1·03 [0·72–1·45], P  =  0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF 13B) expression (n  = 162) had significantly longer mPFS than those with high BAFF expression (n  = 55), using the 75th percentile cut‐off point (mPFS [95% CI ] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI ] = 1·59 [1·11–2·29], P  =  0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.     

Improved outcome for children with non‐high risk acute lymphoblastic leukaemia after using an ALL IC‐BFM 2002‐based protocol in Shanghai,China

We report the outcome of 92 non‐high risk children with acute lymphoblastic leukaemia (ALL) following a Berlin‐Frankfürt‐Münster (BFM) Intercontinental ALL ‐based protocol. Compared with a matched historical control group, we found a lower incidence of treatment‐related early death (1·2% vs. 10·9%, P = 0·015), a higher 6‐year event‐free survival (75·4 ± 4·9% vs. 58·2 ± 6·7%, P = 0·02), reduced total in‐hospital costs per person (US $) (10267·0 vs. 18331·0, P < 0·001) and fewer total in‐hospital days (164 vs. 296, P < 0·001). This ALL‐BFM based protocol was quite tolerable in our institution and will be extended to high‐risk patients.     

Post‐transplantation cyclophosphamide versus conventional graft‐versus‐host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation

Post‐transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft‐versus‐host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy‐based GVHD prophylaxis in human leucocyte antigen (HLA)‐mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high‐risk haematological malignancies who underwent one‐antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti‐thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II–IV (37% vs. 36%, P = 0·8) and grade III–IV (17% vs. 12%, P = 0·5) acute GVHD was similar at day 100. However, the incidence of grade II‐IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0·01). Median time to neutrophil (18 days vs. 12 days, P < 0·001) and platelet (25·5 days vs. 18 days, P = 0·05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2‐year non‐relapse mortality, relapse, progression‐free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA‐MMUD HCT.     

Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia

The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.     

Allogeneic transplantation using CD34+ selected peripheral blood progenitor cells combined with non‐mobilized donor T cells for refractory severe aplastic anaemia

Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA ) unresponsive to immunosuppressive therapy. To reduce chronic graft‐versus‐host disease (GVHD ), which occurs more frequently after peripheral blood stem cell (PBSC ) transplantation compared to bone‐marrow transplantation (BMT ), and to prevent graft rejection, we developed a novel partial T‐cell depleted transplant that infuses high numbers of granulocyte colony‐stimulating factor‐mobilized CD 34⁺ selected PBSC s combined with a BMT ‐equivalent dose of non‐mobilized donor T‐cells. Fifteen patients with refractory SAA received cyclophosphamide, anti‐thymocyte globulin and fludarabine conditioning, and were transplanted with a median 8 × 10⁶ CD 34⁺ cells/kg and 2 × 10⁷ non‐mobilized CD 3⁺ T‐cells/kg from human leucocyte antigen‐matched sibling donors. All achieved sustained engraftment with only two developing acute and two developing chronic GVHD . With a 3·5‐year median follow‐up, 86% of patients survived and were transfusion‐independent. When compared to a retrospective cohort of 56 bone‐marrow failure patients that received the identical transplant preparative regimen and GVHD prophylaxis with the exception that the allograft contained unmanipulated PBSC s, partial T‐cell depleted transplant recipients had delayed donor T‐cell chimerism and relative reduction of 75% in the incidence of acute grade II ‐IV GVHD (13% vs. 52%; P  =  0·010) and of 82% in chronic GVHD (13% vs. 72%; P  =  0·0004). In multivariate analysis, partial T‐cell depleted transplants remained significantly associated with a reduced risk of GVHD . In conclusion, for patients with refractory SAA , this novel transplant strategy achieves excellent engraftment and survival when compared to unmanipulated PBSC transplants and dramatically reduces the incidence of both acute and chronic GVHD .     

Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis

The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10⁹/l at presentation (median WBC 85·5 × 10⁹/l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4‐week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3‐year disease‐free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3‐year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3‐year OS were not significantly improved in patients who received leukapheresis. CR rate and 3‐year OS for the 15 patients with hyperleucocytosis treated with all‐trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non‐ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO‐based combinations are superior to other regimens in these patients.     

Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and anthracycline‐based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline‐based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2‐year overall survival (OS) (P = 0·005) and 2‐year disease‐free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2‐year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71–30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08–0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49–43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05–0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99–1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.     

Increased regulatory T cell graft content is associated with improved outcome in haematopoietic stem cell transplantation: a systematic review

Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft‐versus‐host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta‐analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0·42, 95% confidence interval (CI) 0·23–0·74, P  = 0·003, 2 studies], with a significant reduction in non‐relapse mortality (HR 0·30, 95% CI 0·14–0·64, P  = 0·002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0·59, 95% CI 0·40–0·89, P  = 0·01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice.     

Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan

To evaluate haematopoietic stem cell transplantation (HSCT) in children and adolescents, we reviewed the records of 47 patients who were ≤18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission (CR) was less common in allogeneic HSCT recipients (n = 24) than in autologous HSCT recipients (n = 23) (P = 0·01). The autologous and allogeneic HSCT groups differed in terms of 5‐year event‐free survival (EFS) (38% vs. 50%, P = 0·63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0·25), and treatment‐related mortality (12% vs. 25%, P = 0·40). However, these differences were not significant. Patients with non‐CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0·03). Conversely, although those with non‐CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0·26). Reduced‐intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non‐CR. These three patients achieved CR, surviving 32–65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy.     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.     

CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia

CD 49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL ) cells, and strongly correlates with more aggressive disease. Given its association with cell‐cell adhesion and leucocyte trafficking, we hypothesized that patients with high CD 49d expression would experience a clinical course dominated by lymphadenopathy. CD 49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL /small lymphocytic leukaemia patients; 279 (35%) were CD 49d positive. CD 49d‐positive patients were more likely to present with lymphadenopathy (P  <  0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH ) and IGHV mutation status [odds ratio (OR ) 2·51; 95% confidence interval (CI ) 1·64–3·83; P  <  0·001]. Among CLL Rai 0 patients, CD 49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P  <  0·01). This association was maintained after adjusting for either FISH [hazard ratio (HR ) 2·18; 95% CI 1·25–3·81; P  =  0·006) or IGHV status (HR 2·02; 95% CI 1·11–3·69; P  =  0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88–3·38; P  =  0·11).These data demonstrate that CD 49d‐positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring.     

The efficacy and safety of gemcitabine,cisplatin, prednisone,thalidomide versus CHOP in patients with newly diagnosed peripheral T‐cell lymphoma with analysis of biomarkers

We compared the efficacy and safety of gemcitabine, cisplatin, prednisone and thalidomide (GDPT) with standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with newly diagnosed peripheral T‐cell lymphoma (PTCL) in a prospective randomized controlled and open‐label clinical trial. Between July 2010 and June 2016, 103 patients were randomly allocated into two groups, of whom 52 were treated with GDPT therapy and 51 with CHOP therapy. The 2‐year progression‐free survival (PFS) and overall survival (OS) rates were better in the GDPT group than in the CHOP group (57% vs. 35% for 2‐year PFS, P = 0·0035; 71% vs 50% for 2‐year OS, P = 0·0001). The complete remission rate (CRR) and the overall response rate (ORR) in the GDPT group were higher than in the CHOP group (52% vs. 33%, P = 0·044 for CRR; 67% vs. 49%, P = 0·046 for ORR). Haemocytopenia was the predominant adverse effect, and acute toxicity was moderate, tolerable and well managed in both arms. mRNA expression of ERCC1, RRM1, TUBB3 and TOP2A genes varied among patients but the difference did not reach statistical significance, mainly due to the relatively small sample size. The precise characters of these biomarkers remain to be identified. In conclusion, GDPT is a promising new regimen as potential first‐line therapy against PTCL. This study was registered at www.clinicaltrials.gov as #NCT01664975.     

Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid‐refractory,grade III–IV acute graft‐versus‐host disease

Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid‐refractory, acute graft‐versus‐host disease (aGvHD) but comprehensive data on paediatric patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months‐17 years) treated with MSCs for steroid‐refractory grade III–IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation‐related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0·001). After a median follow‐up of 2·9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0·001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5–85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13–85 d after steroids (25% and 53%, respectively; P = 0·22 and 0·06, respectively). Multiple MSC infusions are safe and effective for children with steroid‐refractory aGvHD, especially when employed early in the disease course.     

Nodular lymphocyte predominant Hodgkin lymphoma in Sweden between 2000 and 2014: an analysis of the Swedish Lymphoma Registry

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent CD20⁺ lymphoma. Its scarcity has made clinical trials difficult and there is no consensus on first‐line treatment. We conducted a population‐based study of all patients diagnosed with NLPHL in Sweden between 2000 and 2014 (N = 158; 41 women and 117 men), focusing on clinical features, therapy and overall survival. The median female and male age was 59 and 44 years, respectively (P = 0·002). In early‐stage disease, there was little mortality and no survival differences between therapies. In patients with advanced‐stage disease, mortality was relatively high in patients who did not receive first‐line rituximab but absent in those who did (10‐year survival, 55% vs. 100%; P = 0·033); there were no imbalances of prognostic factors between those two groups. In advanced stages, first‐line rituximab use increased markedly between 2000–2004 and 2005–2014 (7% vs. 67%; P < 0·00005), as did 10‐year survival, 53% vs. 72% (multivariate P = 0·027). Although all patients were diagnosed in the 2000s, this is the longest‐followed (and largest) population‐based cohort. We report a hitherto unreported 15‐year median age difference between sexes, increasing rituximab use and improved survival.     

TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis

Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS‐F). Expression of TP53 was evaluated in BM core biopsy specimens using dual‐colour CD34/TP53 immunohistochemistry with computer‐assisted image analysis. Mutation analysis was performed using next‐generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high‐ and very‐high risk IPSS‐R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34‐positive cells was associated with shorter OS and leukaemia‐free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS‐F.     

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta‐analysis

This systematic review and meta‐analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty‐nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66–0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51–0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91–1·16; P = 0·63). Higher‐dose DNR, compared to lower‐dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60–0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75–0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high‐dose DNR (90 mg/m² daily × 3 or 50 mg/m² daily × 5) and IDA (12 mg/m² daily × 3) can achieve 5‐year survival rates of between 40 and 50 percent.