OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma.

Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2-4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.

Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population.

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma--a retrospective population based study of 1162 patients.

The combination of melphalan and prednisone (MP) has been the standard treatment of multiple myeloma (MM). Since the introduction of novel agents, the clinical outcome in MM has improved. Six randomized prospective studies with thalidomide combined with melphalan and prednisone (MPT) compared to MP have been performed, most of them showing that MPT gives a better response rate and median overall survival (OS). Amongst 1843 MM patients admitted to 15 Swedish centres, we selected all patients treated with MP and MPT in first, second, third or fourth line of therapy, in total 888 patients treated with MP and 274 with MPT. Patients were evaluated for response rate, OS and Time to Next Treatment. Multivariate Cox model analysis was made to adjust for different criteria at time for MM-diagnosis. The median OS from beginning of first line of treatment was 2.2/4.2 yrs after MP/MPT respectively, and in second, third and fourth line of treatment 1.8/2.9, 1.4/1.6 and 1.1/1.9 yrs (P < 0.0001, 0.003, 0.74 and 0.235). The relative risk for death in the MPT group vs. the MP group was 0.61 (95% CI: 0.45-0.84) in first and 0.55 (0.38-0.83), P < 0.01) in second line. Treatment with MPT gave a significantly better OS rate after both first and second line of therapy when compared with treatment with MP only.

A combination regimen of bortezomib, cyclophosphamide and betamethasone gives quicker, better and more durable response than VAD/CyBet regimens: results from a Swedish retrospective analysis.

BACKGROUND: Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined. METHODS: We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT. RESULTS: One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression. CONCLUSIONS: Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage.

The cost-effectiveness of bortezomib in relapsed/refractory multiple myeloma: Swedish perspective.

OBJECTIVES: To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/DEX) for the treatment of relapsed/refractory multiple myeloma in Sweden. METHODS: We used partitioned survival analysis to assess survival data decomposed into three states: (i) alive before disease progression; (ii) alive after progression; and (iii) dead. The effects of treatment on time to progression and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. RESULTS: BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN/DEX, respectively. Mean lifetime direct medical costs per patient were approximately 2010 SEK 1,904,462, 1,278,854, and 2,450,588 for BTZ, DEX, and LEN/DEX, respectively. Mean incremental cost per quality-adjusted life-year of BTZ compared to DEX was 2010 SEK 902,874 (€95,073) (95% CI: 514,791, 962,416) and was dominant with respect to LEN/DEX. CONCLUSION: BTZ and LEN/DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN/DEX.

Evaluation of immune responses to seasonal influenza vaccination in healthy volunteers and in patients after stem cell transplantation.

BACKGROUND: Influenza causes significant morbidity and mortality in immunocompromised stem cell transplantation (SCT) recipients. Measurement of cellular and humoral immunological responses might increase our understanding of how to estimate a protective response to influenza vaccination. METHODS: Eighteen healthy subjects and 14 SCT patients tested before and 4 weeks after influenza vaccination were included in the study. Peripheral blood lymphocytes were stimulated with influenza peptides and Enzyme-Linked ImmunoSpot assays to measure the production of intracellular interferon-gamma, interleukin-4 and interleukin-13. Prelabeled major histocompatibility complex class I pentamers were used for the detection of influenza-specific CD8+ T-cells. B-cell Enzyme-Linked ImmunoSpot and hemagglutination inhibition assays were performed to enumerate influenza-specific antibody-secreting cells and titer of neutralizing antibodies. RESULTS: Influenza vaccination elicited strong cell-mediated immune responses in the healthy controls (P< or =0.003 for all four peptides) and SCT patients (P< or =0.008). The percentage of CD8+ specific cells increased significantly after vaccination both in volunteers (P=0.005) and in patients (P< or =0.003). The number of influenza-specific antibody-secreting cells increased after vaccination both in volunteers (P=0.009) and in patients (P=0.01). Twenty-nine percent of SCT patients demonstrated protective antibody levels to influenza A H1/N1 serotype. CONCLUSIONS: Seasonal vaccination against influenza boosts the cellular immune response both in SCT patients and healthy controls. The protective effect is lower in the patients in general and especially on those, vaccinated early after SCT.

Risk assessment in haematopoietic stem cell transplantation: conditioning.

After the introduction of cyclophosphamide and total body irradiation in the 1970s, a variety of conditioning regimens has been developed. However, none has proven to be superior. Fractionation of the irradiation results in less toxic side-effects, but the total dose has to be increased to obtain similar immunosuppressive effects. Data from randomized trials indicate that among patients with myeloid leukaemia, busulfan in combination with cyclophosphamide results in similar outcome, while a regimen containing total body irradiation is probably still the best for patients with acute lymphoblastic leukaemia. Busulfan treatment can be optimized by targeted steady-state concentration or with the use of intravenous preparations. Intensified regimens decrease the relapse incidence, but because of a higher mortality from transplant-related causes survival is unchanged. Reduced-intensity conditioning can reduce transplant-related mortality and offer otherwise ineligible patients a potentially curative treatment. Long-term results are unknown.

Myeloablative and immunosuppressive properties of treosulfan in mice.

OBJECTIVE: Treosulfan is a prodrug with a specific clinical activity in ovarian carcinoma and other solid tumors. Due to its myeloablative and immunosuppressive effects, its use in conditioning regimens prior to allogeneic stem cell treatment (SCT) has been proposed. In the present preclinical study, myeloablative as well as immunosuppressive properties of treosulfan were compared with those of busulfan and cyclophosphamide. METHODS: Three groups of BALB/c mice were treated with treosulfan, cyclophosphamide, or busulfan at sublethal doses that maintained survival without bone marrow support. The control group was left untreated. At different intervals, colony-forming unit granulocyte macrophage assay was performed on marrow cells. Additionally, immunological analyses were performed using spleen cells. RESULTS: We found that treosulfan and busulfan induced a high and persisting degree of myeloablation, as compared with cyclophosphamide. Moreover, treosulfan was more effective in depletion of splenic B and T cells in comparison with busulfan and cyclophosphamide. Furthermore, T cells isolated from the spleens of treosulfan- or busulfan-treated mice were not responsive to allogeneic cells compared with that observed in controls and cyclophosphamide-treated mice. Treatment with treosulfan induced only interleukin-2 production in spleen cells for a short time and had no significant effect on synthesis of tumor necrosis factor-alpha and/or interferon-gamma as compared with that observed in splenic T cells isolated from mice treated with either busulfan or cyclophosphamide. CONCLUSION: Our findings suggest that treosulfan possesses both myeloablative and immunosuppressive properties and may be used as a single agent for conditioning prior to bone marrow transplantation.

Allogeneic hematopoietic stem cell transplantation for inherited disorders: experience in a single center.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders. METHODS: We report 20 years of experience in 71 patients. The disorders include 7 immunodeficiencies, 21 hematological disorders, 13 histiocytic disorders, 9 mucopolysaccharoidoses, 7 metachromatic leukodystrophies (MLD), 3 adrenoleukodystrophies (ALD), 2 adrenomyeloneuropathy (AMN), 6 patients with Gaucher's disease, 1 Sandhoff's disease, and 2 patients with aspartylglucosaminuria. Their median age was 4 (0-39) years. The donors were 29 HLA-identical related, 27 matched unrelated (MUD) and 15 HLA mismatches. RESULTS: In recipients of HLA-identical sibling grafts, none developed acute GVHD grades II-IV as against 22% in all others. The overall cumulative incidence of chronic GVHD was 17%. The 5-year survival rates were 93%, 84%, and 46% in recipients of grafts from HLA-identical siblings, MUD and HLA-mismatches, respectively. The overall 10-year survival rate was 69%. All of the surviving patients with immunodeficiencies and hemoglobinopathies are well. Four patients with Hurler's disease are also well, apart from skeletal problems. Five patients with Gaucher's disease are between 14 and 22 years after the transplant. Two infants with MLD deteriorated, a girl with the juvenile form has stable disease and one woman with the adult form has improved. Among four survivors with ALD/AMN, three are well and one has dementia. Two patients with aspartylglucosaminuria have stable disease. CONCLUSION: In patients with inborn errors of metabolism, ASCT gives a high survival rate using HLA-matched donors. Beneficial effects are seen in those who are transplanted early.

Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.

BACKGROUND: Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD). METHODS: We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors. RESULTS: Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma. CONCLUSION: MSC is a very promising treatment for severe steroid-resistant acute GVHD.

Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation.

BACKGROUND AND OBJECTIVES: Cytomegalovirus (CMV) disease remains an important complication of allogeneic stem cell transplantation (SCT). We studied viral load kinetics and correlated the viral load and other transplant factors with the development of CMV disease. DESIGN AND METHODS: We studied 162 consecutive patients who were CMV seropositive or had CMV seropositive donors. Quantification of CMV DNA was performed by real-time polymerase chain reaction. RESULTS: CMV DNA detected was detected in 105 of the 162 patients. The mean peak viral loads were similar at first and subsequent reactivations. The serologic status of the donors and recipients prior to SCT significantly influenced the viral load. The cumulative incidence of CMV disease was 1.8% at 100 days and 6.3% at 365 days after SCT. The peak viral load were higher in patients who developed CMV disease than in patients without CMV disease (log10 3.5; SE +/- 0.26/200,000 cells vs. log10 2.7; SE +/- 0.09/200,000 cells; p=0.02). However, in multivariate analysis, only acute graft-versus-host disease (GVHD) grade II-IV and a graft from a CMV-negative donor to a CMV-positive patient were significant risk factors for CMV disease. In patients who required more than one course of pre-emptive therapy, acute GVHD and the rate of decrease in viral load during first pre-emptive therapy were significant risk factors for subsequent development of CMV disease. INTERPRETATION AND CONCLUSIONS: A decrease in viral load during pre-emptive therapy is an important factor for later development of CMV disease.

Reduced risk for extensive chronic graft-versus-host disease in patients receiving transplants with human leukocyte antigen-identical sibling donors given polymerase chain reaction-based preemptive therapy against cytomegalovirus.

BACKGROUND: The aim of this study was to investigate the relationship between cytomegalovirus (CMV) and extensive chronic graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation (SCT). METHODS: Two hundred sixty-two consecutive patients undergoing conventional SCT with human leukocyte antigen-identical sibling donors, given cyclosporine A and methotrexate as GvHD prophylaxis and surviving more than 3 months after SCT, were retrospectively analyzed. Most patients received transplants because of a hematologic malignancy (n=226), but 36 patients with nonmalignant disorders were included in the analysis. Ninety-nine patients were monitored for CMV infection with rapid virus isolation and 163 patients by either a pp65 antigenemia test (n=5) or a qualitative polymerase chain reaction (PCR) assay for CMV-DNA (n=158). RESULTS: One hundred thirty (50%) of the patients developed chronic GvHD, of whom 17 (6.5%) developed extensive chronic GvHD. Risk factors for development of extensive chronic GvHD were determined by multivariate logistic regression. The strategy of PCR-based monitoring for CMV-DNA, giving preemptive antiviral therapy on demand, significantly decreased the risk for developing extensive chronic GvHD (odds ratio=0.32, P =0.03). No other factors tested, including recipient and donor age and sex, source of graft, cell dose, and acute GvHD, had any significant effect on the development of extensive chronic GvHD. CONCLUSIONS: We conclude that the risk for extensive chronic GvHD in this homogenous group of patients was reduced by the use of PCR-based preemptive therapy.

Clinical tolerance after allogeneic hematopoietic stem cell transplantation: a study of influencing factors.

BACKGROUND: Clinical tolerance, defined as discontinuation of immunosuppression without immunological events, is often achieved after allogeneic hematopoietic stem cell transplantation, unlike after organ transplantation. However, this phenomenon has rarely been studied. METHODS: Between September 1977 and December 1997, we evaluated 354 allogeneic hematopoietic stem cell recipients who had had more than 1 year of relapse-free survival, regarding time to discontinuation of immunosuppression. Factors such as patient age, donor age, donor sex, immunosuppressive protocols, cell dose, and graft-versus-host-disease (GVHD) were studied. RESULTS: Patients who did not develop GVHD had discontinued immunosuppression according to the protocols, within 1 year for malignant diseases and within 2 years for nonmalignant diseases. Patients given methotrexate as a single drug were off immunosuppression faster than those given cyclosporine alone (P=0.05). Children (<18 years) discontinued immunosuppression faster than adults (P=0.05). Low donor age was of greater importance than low recipient age for early discontinuation (P=0.003). Male recipients of stem cells from immunized female donors needed a longer time to discontinuation (P<0.001). Patients without acute GVHD had a shorter time to discontinuation than patients with any grade of GVHD (P=0.02). Thirteen months after hematopoietic stem cell transplantation, 54% of HLA-identical sibling marrow recipients and 36% of unrelated marrow recipients with malignant disease had discontinued immunosuppression (P=0.002). Twenty-five months after hematopoietic stem cell transplantation, the corresponding figures were 69% and 75% in the two groups, respectively. CONCLUSION: In multivariate analysis, high donor age, immunized female donor to male recipient, and grades II-IV acute GVHD were significantly associated with a longer time to clinical tolerance.

The use of novel drugs can effectively improve response, delay relapse and enhance overall survival in multiple myeloma patients with renal impairment.

BACKGROUND: Renal impairment is a common feature in multiple myeloma and is considered a poor prognostic factor. AIM: To determine the impact of novel drugs (i.e. bortezomib, lenalidomide and thalidomide) in the treatment of myeloma patients with renal impairment. The primary endpoint was overall survival and secondary endpoints were time to next treatment and response. METHODS: The study population included all patients diagnosed with treatment-demanding multiple myeloma January 2000 to June 2011 at 15 Swedish hospitals. Renal impairment was defined as an estimated glomerular filtration rate under 60 mL/min/1.73 m2. RESULT: The study population consisted of 1538 patients, of which 680 had renal impairment at diagnosis. The median overall survival in patients with renal impairment was 33 months, which was significantly shorter than 52 months in patients with normal renal function (P<0.001). Novel agents in first line improved overall survival (median 60 months) in non-high-dose treated patients with renal impairment (n = 143) as compared to those treated with conventional cytotoxic drugs (n = 411) (median 27 months) (P<0.001). In the multivariate analysis up front treatment with bortezomib was an independent factor for better overall survival in non-high-dose treated renally impaired patients. High-dose treated renally impaired patients had significantly better median overall survival than non-high-dose ones (74 versus 26 months) and novel drugs did not significantly improve survival further in these patients. Patients with renal impairment had both a shorter median time to next treatment and a lower response rate than those with normal renal function. However, novel drugs and high dose treatment lead to a significantly longer time to next treatment and the use of novel agents significantly improved the response rate of these patients. CONCLUSION: High dose treatment and novel drugs, especially bortezomib, can effectively overcome the negative impact of renal impairment in patients with multiple myeloma.

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning.

PURPOSE: Treosulfan was introduced recently as a conditioning agent for allogeneic blood stem-cell transplantation. The favorable nonhematologic toxicity profile at 3 x 10 g/m(2) was the basis for dose escalation in this prospective, multicenter trial. PATIENTS AND METHODS: Fifty-six patients with various hematologic malignancies who were not eligible for standard conditioning were treated with one of three doses: 10 g/m(2), 12 g/m(2), or 14 g/m(2) of intravenous treosulfan, which was administered on days -6 to -4 combined with fludarabine 30 mg/m(2) on days -6 to -2. Patients in complete remission (CR; 42%) or non-CR (58%) received grafts from matched related (47%) or matched unrelated (51%) donors; one patient had a mismatched related donor (2%). RESULTS: No engraftment failure occurred. Overall, extramedullary toxicity and the nonrelapse mortality rate at 2 years (20%) were low and did not increase with dose. Cumulative incidence of relapse/progression reached 31%. The overall survival and progression-free survival rates were 64% and 49%, respectively, in the total study population. An inverse dose dependency of relapse incidence was indicated in the subgroup receiving transplantations from matched related donors (P = .0568). CONCLUSION: Treosulfan-based conditioning was feasible at all three doses. The 3 x 14 g/m(2) dose was selected for additional studies, because it combines desired characteristics of low toxicity and a low relapse rate.

Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: a phase I clinical study.

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.

Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis.

We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.

Hemorrhagic cystitis: a retrospective single-center survey.

Severe hemorrhagic cystitis (HC) may be a life-threatening complication in allogeneic stem cell transplantation (SCT). In order to improve the strategies for prophylaxis and treatment, we retrospectively analyzed data on patients who underwent SCT at our center from 1990 through 2005. Patients with HC were identified through our database and their medical charts were reviewed. Grades 2-5 and 3-5 HC developed in 109/834 patients (13.1%) and 27/834 patients (3.2%), respectively. The frequency of HC decreased over the time from 18.0% in 1990-1992 to 9.5% in 2002-2005 (p = 0.005). HC started on a median of 35 (0-166) days post-transplant and persisted for a median of 23 (2-270) days. Transplant-related mortality was 21% in patients without HC, 15% in those with HC of grade 2, 55% in those with grade 3, and 71% in patients with HC of grades 4-5 (p < 0.001). In multivariate analysis, the risk factors for HC were myeloablative conditioning, busulphan, cytomegalovirus infection, hematological malignancy, and acute graft-versus-host disease (aGVHD). With four risk factors, the risk of HC development was 31%. Risk factors for severe HC of grades 3-5 were aGVHD and bacteremia.

Allogeneic haematopoietic stem cell transplantation: current status and future outlook.

Allogeneic haematopoietic stem cell transplantation (allo-SCT) is an established treatment of haematological malignancies and other immunohaematopoietic disorders. The use of unrelated donors and cord blood (CB) grafts has increased the possibilities of finding a donor, and results are approaching those after sibling donor transplants. The use of peripheral blood stem cells (PBSCs), instead of bone marrow, results in faster engraftment and increased risk of chronic graft-versus-host disease (GVHD). High-dose myeloablative (MA) conditioning is recently challenged by reduced-intensity conditioning (RIC) for older patients and those with comorbidity. Better diagnostic tools and novel anti-microbial drugs have reduced morbidity and mortality from infections. A major problem is disease relapse. Early detection of minimal residual disease or recurrent recipient haematopoietic cells allows early intervention with immunotherapy. Donor lymphocyte infusions (DLIs) have not only an anti-leukaemic effect but also an anti-tumour effect against a variety of solid organ tumours. New indications such as metastatic solid tumours are investigated. Mesenchymal stem cells (MSC) may enhance engraftment and have immunomodulatory effects.