What is the outcome in patients with acute leukaemia who survive severe acute graft-versus-host disease?

BACKGROUND: Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (HSCT). With new promising therapies, survival may improve for severe aGVHD. OBJECTIVES: We wanted to analyze the long-term outcome in patients who survive severe aGVHD. METHODS: This study was a landmark analysis of 23 567 patients with acute Leukaemia who survived for more than 6 months after HSCT, 2002-2014. Patients alive after severe aGVHD (n = 1738) were compared to controls. RESULTS: Patients with severe aGVHD had higher non-relapse mortality (NRM) and higher rate of extensive chronic GVHD (cGVHD) than the controls (P < 10-5 ). The probability of relapse was significantly lower in the severe aGVHD group, but Leukaemia-free survival (LFS) and overall survival were significantly lower than for the controls (P < 10-5 ). Five-year LFS in patients with severe aGVHD was 49%, as opposed to 61% in controls with no or mild GVHD and 59% in patients with moderate GVHD. CONCLUSIONS: HSCT patients who survive severe aGVHD have higher risk of developing extensive cGVHD, a higher NRM, a lower relapse probability, and lower LFS than other HSCT patients. This study is a platform for outcome analysis in patients treated with novel therapies for acute GVHD.

Prognostic pre-transplant factors in myelodysplastic syndromes primarily treated by high dose allogeneic hematopoietic stem cell transplantation: a retrospective study of the MDS subcommittee of the CMWP of the EBMT.

Many pre-transplant factors are known to influence the outcome of allogeneic stem cell transplantation (SCT) treatment in myelodysplastic syndromes (MDS). However, patient cohorts are often heterogeneous by disease stage and treatment modalities, which complicates interpretation of the results. This study aimed to obtain a homogeneous patient cohort by including only de novo MDS patients who received upfront allogeneic SCT after standard high dose myelo-ablative conditioning. The effect of pre-transplant factors such as age, disease stage, transfusions, iron parameters and comorbidity on overall survival (OS), non-relapse mortality (NRM), and relapse incidence (RI) was evaluated in 201 patients. In this cohort, characterized by low comorbidity and a short interval between diagnosis and transplantation, NRM was the most determinant factor for survival after SCT (47 % after 2-year follow-up). WHO classification and transfusion burden were the only modalities with a significant impact on overall survival after SCT. Estimated hazard ratios (HR) showed a strongly increased risk of death, NRM and RI, in patients with a high transfusion-burden (HR 1.99; P = 0.006, HR of 1.89; P = 0.03 and HR 2.67; P = 0.03). The HR's for ferritin level and comorbidity were not significantly increased.

Cellular uptake of coumarin-6 under microfluidic conditions into HCE-T cells from nanoscale formulations.

UNLABELLED: In vitro studies of ocular bioavailability of active pharmaceutical ingredients (API) from colloidal drug delivery systems do not consider physiological shear stress generated by eyelid wiping and tear flow. The present study introduces a live cell imaging approach which enables the investigation of model drug uptake from various formulations under shear stress by using custom-made microchannels for the cultivation of human corneal epithelial cells (HCE-T). Coumarin-6 (C-6) was used as a model API incorporated into solid lipid nanoparticles and liposomes, and as an aqueous crystalline suspension. Confocal laser scanning microscopy visualized C-6 uptake into HCE-T cells in a time-resolved manner with an applied shear stress of 0.1 Pa. Static conditions were also studied for comparative purposes. Additionally, solid lipid nanoparticles (SLN) were labeled with a fluorescent phospholipid to check whether C-6 uptake was associated with SLN incorporation into the cells. RESULTS: Intact SLN were not incorporated into the cells, i.e., C-6 was passively redistributed from SLN to lipophilic cellular compartments. C-6 was enriched up to a given limit in HCE-T cells within 5 min of contact with the dispersions both under static and under flow conditions. The C-6 delivery rate from liposomes was superior to that from SLN whereby the suspension exhibited the lowest rate. C-6 release rates were comparable for static and flow conditions. Alternate flushing with formulations and buffer revealed that cells accumulated C-6. The results suggest that combining microfluidics with live cell imaging provides a valuable option for in vitro studies of ocular drug delivery.

Outcome and prognostic factors in patients with mantle-cell lymphoma relapsing after autologous stem-cell transplantation: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT).

BACKGROUND: Autologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting. PATIENTS AND METHODS: Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients. RESULTS: Median overall survival (OS) after relapse of the whole study group was 19 months. A long (>12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis. Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation. CONCLUSIONS: MCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.

Sequential vs myeloablative vs reduced intensity conditioning for patients with myelodysplastic syndromes with an excess of blasts at time of allogeneic haematopoietic cell transplantation: a retrospective study by the chronic malignancies working party of the EBMT.

The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status.

In vitro and ex vivo toxicological testing of sildenafil-loaded solid lipid nanoparticles.

The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) loaded with sildenafil. The SLNs were tested as a new drug delivery system (DDS) for the inhalable treatment of pulmonary hypertension in human lungs. Solubility of sildenafil in SLN lipid matrix (30:70 phospholipid:triglyceride) was determined to 1% sildenafil base and 0.1% sildenafil citrate, respectively. Sildenafil-loaded SLN with particle size of approximately 180 nm and monomodal particle size distribution were successfully manufactured using a novel microchannel homogenization method and were stable up to three months. Sildenafil-loaded SLN were then used in in vitro and ex vivo models representing lung and heart tissue. For in vitro models, human alveolar epithelial cell line (A459) and mouse heart endothelium cell line (MHEC5-T) were used. For ex vivo models, rat precision cut lung slices (PCLS) and rat heart slices (PCHS) were used. All the models were treated with plain SLN and sildenafil-loaded SLN in a concentration range of 0-5000 µg/ml of lipid matrix. The toxicity was evaluated in vitro and ex vivo by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Median lethal dose 50% (LD50) values for A549 cells and PCLS were found to be in the range of 1200-1900 µg/ml while for MHEC5-T cells and precision cut heart slices values were found between 1500 and 2800 µg/ml. PCHS showed slightly higher LD50 values in comparison to PCLS. Considering the toxicological aspects, sildenafil-loaded SLN could have potential in the treatment of pulmonary hypertension via inhalation route.

Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study.

BACKGROUND: High-dose chemotherapy followed by autologous stem-cell transplantation (HCT-ASCT) is a promising approach in eligible patients with primary central nervous system lymphoma (PCNSL). We report long-term data of patients who were treated according to HCT-ASCT containing protocols. PATIENTS AND METHODS: We analyzed survival and relapse rates in 43 (<67 years) immunocompetent patients with newly diagnosed PCNSL being treated according to two different high-dose methotrexate-based protocols followed by high-dose carmustine/thiotepa (BCNU/TT) plus ASCT (±whole brain irradiation). Analysis was conducted for all patients (intention-to-treat) and those patients who actually received HCT-ASCT (per-protocol). RESULTS: Thirty-four patients achieved complete remission, of those 12 relapsed (35%), while 6 of them relapsed 5 years after diagnosis. After a median follow-up of 120 months, median overall survival (OS) was reached after 104 months. Two- and 5-year OS was 81% and 70% and 2- and 5-year event-free survival (EFS) was 81% and 67%, respectively. In per-protocol analysis (N = 34), 5-year OS and EFS was 82% and 79%, respectively. HCT-ASCT associated related mortality was not observed. CONCLUSIONS: Sequential high-dose MTX containing chemotherapy followed by high-dose carmustine/thiotepa plus ASCT (±whole brain irradiation) is safe and leads to high survival rates in eligible patients with newly diagnosed PCNSL.

Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma.

BACKGROUND: To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. RESULTS: At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). CONCLUSION: Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients.

BACKGROUND: No survival benefit of using blood stem cells instead of bone marrow (BM) has been shown in matched unrelated donor (MUD) transplantation. DESIGN AND METHODS: In a retrospective registry analysis, we compared the use of blood stem cells (n = 1502) and BM (n = 760) from unrelated donors in patients aged 18-60 years with acute myeloid leukaemia (AML) undergoing myeloablative conditioning between 1997 and 2008. The blood stem cell recipients were older (P < 0.01), had more advanced disease (P < 0.0001) and received less total body irradiation (P < 0.0001) and more antithymocyte globulin (P = 0.01). RESULTS: Recovery of neutrophils and platelets was faster with blood stem cells (P < 0.0001). The incidence of acute graft-versus-host disease (GVHD) was similar, but there was more chronic GVHD in the blood stem cell group [hazard ratio (HR) = 1.29, P = 0.02]. There were no significant differences in nonrelapse mortality (NRM), relapse incidence and leukaemia-free survival (LFS) between the two groups amongst patients with AML in remission. In patients with advanced leukaemia, NRM was lower (HR = 0.61, P = 0.02) and LFS was prolonged (HR = 0.67, P = 0.002) when blood stem cells were used. At 3 years, LFS for all patients, regardless of remission status, was 41% for both treatment groups. The outcome was not affected after multivariable analysis adjusted for confounders. CONCLUSION: Blood stem cells compared with BM in MUD transplantation for patients with AML in remission resulted in the same rates of LFS. In patients with advanced leukaemia, the blood stem cell group had reduced NRM and improved LFS.

[Current diagnostics and therapy of B cell Non Hodgkin Lymphoma]. / Aktuelle Diagnostik und Therapie bei B-Zell Non Hodgkin Lymphomen.

New diagnostic tools and therapeutic options for Non Hodgkin Lymphoma (NHL) contributed to several improvements in the understanding and treatment of this hematological malignancies. In diffuse large cell lymphoma (DLBCL) gene expression profiling and molecular analyses of myc and bcl-2 gene rearrangements resulted in the description of new DLBCL entities with significant differences in outcome. Combination immunochemotherapy according to the R-CHOP protocol remains the mainstay for treatment of DLBCL in younger and older patients. Mantle cell lymphoma is characterised by the overexpression of cyclin D1. While older patients should be treated with R-CHOP with rituximab maintenance therapy, first line treatment of younger patients should also include AraC containing regimens and autologous stem cell transplantation. Cases with follicular lymphoma very often show the t(14; 18) translocation resulting in overexpression of BCL2 and diminished apoptosis. Compared to R-CHOP treatment new combinations with R-Bendamustin have shown high efficacy with reduced toxicity and should therefore be regarded as standard in patients in need for therapy.

Comparison of TWA and PEP as indices of α2- and ß-adrenergic activation.

RATIONALE: Pre-ejection period (PEP) and T-wave amplitude (TWA) have been used to assess sympathetic nervous system (SNS) activity. Here we report two single-blinded, placebo-controlled intravenous (IV) drug application studies in which we pharmacologically modified SNS activity with epinephrine (study 1) as well as dexmedetomidine (alpha2-agonist) and yohimbine (alpha2-antagonist) (study 2). Restricted heart rate (HR) intervals were analyzed to avoid confounding effects of HR changes. OBJECTIVE: Study 1 served to replicate previous findings and to validate our approach, whereas study 2 aimed to investigate how modulation of central SNS activity affects PEP and TWA. METHODS: Forty healthy volunteers (58% females) participated in study 1 (between-subject design). Twelve healthy men participated in study 2 (within-subject design). TWA and PEP were derived from ECG and impedance cardiography, respectively. RESULTS: Epinephrine shortened PEP and induced statistically significant biphasic TWA changes. However, although the two alpha2-drugs significantly affected PEP as expected, no effects on TWA could be detected. CONCLUSION: PEP is better suited to reflect SNS activity changes than TWA.

Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system. In this article, we report the results of a pilot trial adding rituximab to the established regimen consisting of methotrexate, procarbazine, and lomustine (R-MCP). DESIGN AND METHODS: PCNSL patients ≥65 years without Karnofsky performance score (KPS) limit were included. R-MCP regimen consisted of rituximab (375 mg/m(2) i.v. on days -6, 1, 15, and 29), methotrexate (3 g/m(2) i.v., days 2, 16, and 30) followed by folinic rescue, procarbazine (60 mg/m(2) orally, days 2-11), and lomustine (110 mg/m(2) orally, day 2). A maximum of three 43-day cycles were applied. Primary end point was response to treatment obtained by magnetic resonance imaging. Secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Twenty-eight patients were included (median age 75, median KPS 60%). Best documented response: complete remission in 18 of 28 (64%), partial remission in 5 of 28 (18%), stable disease in 1 of 28 (4%), and progressive disease in 2 of 28 (7%) patients. Response was not assessed in two patients. Two treatment-associated deaths were observed. After a median follow-up of 36 months, the 3-year PFS and OS was 31%. CONCLUSION: R-MCP regimen is well tolerated and active in elderly patients with newly diagnosed PCNSL.

Prognostic factors for survival after allogeneic transplantation in acute lymphoblastic leukemia.

Allogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°-IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades.

Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT.

Systemic anaplastic large cell lymphoma (sALCL) is a rare histological entity expressing the CD30 antigen that comprises around 11% of peripheral T-cell lymphoma. We analysed the outcome of patients with relapsed/refractory sALCL treated with autologous stem cell transplantation (auto-HCT). We included 65 adult patients (42 males; median age, 44 years); 24 patients had an ALK-ve sALCL. Fifty-one patients had chemosensitive disease at the time of transplant. Ten patients (15%) were treated with brentuximab vedotin (BV) before auto-HCT (median number of doses: 5). The median follow-up for surviving patients was 35 months (3-71). Three-year cumulative incidence of nonrelapse mortality and of relapse were 1.7% and 34%, respectively. Three-year progression-free survival and overall survival were 64% and 73%, respectively. No prognostic factors for any of the outcomes analysed were found in univariate analysis. There were no significant differences in any of the outcomes between patients who had received BV and the remainder. This is the largest analysis presented so far analysing the role of auto-HCT in patients with relapsed/refractory sALCL, showing a promising PFS and OS in this high-risk population. The potential impact of the administration of BV as salvage strategy before the procedure needs to be further elucidated.

High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study.

BACKGROUND: To improve survival of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a phase II study with high-dose methotrexate (MTX) combined with procarbazine and CCNU. To reduce neurotoxicity, whole-brain irradiation was reserved for patients not responding to chemotherapy. PATIENTS AND METHODS: High-dose MTX was applied on days 1, 15, and 30, procarbazine on days 1-10, and CCNU on day 1. Study treatment comprised up to three 45-day cycles. There was no lower limit of Karnofsky performance status (KPS). RESULTS: Thirty patients with PCNSL (n = 29) or primary ocular lymphoma (n = 1) were included (median age 70 years, range 57-79 years). The median initial KPS was 60% (range 30%-90%). Best documented response in 27 assessable patients were 12 of 27 (44.4%) complete remissions, 7 of 27 (25.9%) partial remissions, and 8 of 27 (29.6%) disease progressions. Two patients died of probable treatment-related causes. With a median follow-up of 78 months (range 34-105), the 5-year overall survival is 33%. Eight of 30 patients (26.7%) are currently alive and well, six without signs of leukoencephalopathy. CONCLUSION: The combination of high-dose MTX with procarbazine and CCNU is feasible and effective and results in a low rate of leukoencephalopathy. Comorbidity and toxicity remain of concern when treating PCNSL in elderly patients.

Placental mononuclear phagocytes as a source of interleukin-1.

Mouse and human placental tissue contains a large number of mononuclear phagocytes. These cells, isolated from placenta, were shown to produce the multifaceted immune factor interleukin-1. Activity in the supernatants of 48-hour mononuclear phagocyte cultures was associated with a 12,000- to 18,000-dalton protein, consistent with known interleukin-1 characteristics. Stimulation of phagocytosis with latex beads increased the production and release of interleukin-1 from these placental cells, which may be a useful source of this protein.

EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL).

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.

A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation.

We present a phase II study of fludarabine 5 x 30 mg/m(2), thiotepa 3 x 5 mg/kg as preparative regimen specifically for allogeneic second haematopoietic stem cell transplantation (HCT) after failure of previous HCT. Forty-nine patients (median age 52 years, range 27-68) received an allogeneic second HCT after failed autologous (n=29) or allogeneic (n=20) HCT. Diagnoses were AML (n=18), ALL (n=3), multiple myeloma (n=11), lymphoma (n=16) and CML (n=1). GVHD prophylaxis consisted of CYA and mainly low dose alemtuzumab (40 mg). The median follow-up for patients alive is 528 days (range 217-1344). In 43 of 49 (88%) evaluable patients response rates were CR=19, PR=14 and SD=10 at one month. At one year, the probability (95% confidence interval) of relapse is 55.1 (38.2-72)% and the nonrelapse mortality (NRM) is 29 (14.2-44.4)%. Estimated survival at one year is 42.6 (28.7-56.6)% and event free survival is 38.1 (24.4-51.8)%. Survival was significantly better for patients experiencing relapse beyond one year, than for patients relapsing within one year from first transplantation (51.2 (33.5-68.9)% vs 27 (7-48.5)%; P=0.013). We conclude that this regimen is feasible and well tolerated for allogeneic second HCT.

Viewpoint: What is the role of allogeneic haematopoietic cell transplantation in the era of reduced-intensity conditioning--is there still an upper age limit? A focus on myeloid neoplasia.

Allogeneic haematopoietic cell transplantation (HCT) is the most effective curative therapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Incidence of AML and MDS increases with age, peaking in the seventh decade. Despite improved Ara-C and anthracyclin-based chemotherapy regimens, the prognosis of AML in patients beyond 60 years of age is dismal. The introduction of peripheral blood-derived stem cell grafts into allogeneic HCT and the known anti-leukaemic effect of donor lymphocyte infusions paved the way for reduced-intensity conditioning (RIC) allogeneic stem-cell transplantation, which makes transplant in advanced age possible and significantly reduces transplant-related organ toxicity and mortality. The success of RIC HCT relies on the alloreactivity of the donor immune system and the graft-versus-leukaemia effect. We try to answer the following questions in this paper: who should receive RIC HCT? when and how should the transplant be performed? is there an upper age limit and what is the future of RIC HCT?