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Acute lymphoblastic leukaemia (ALL) with the t(4;11) translocation has a very poor prognosis following conventional chemotherapy. Many patients are offered an allogeneic BMT in first remission. We report on the impact of allogeneic BMT on three patients with t(4;11) ALL in first remission. Median age was 20 years. One patient received marrow from an HLA-identical sibling and the other two from unrelated donors. All three engrafted and none of the patients developed acute or chronic GVHD. Remission status was monitored using a sensitive nested RT-PCR to detect the ALL-1/AF-4 hybrid transcript. All three were PCR-negative at 3 months post-BMT. One of the unrelated recipients died of a fungal infection 4 months post-BMT. The other two are alive and in molecular remission at 21 and 24 months post-BMT. This is the first report of longitudinal follow-up of t(4;11) ALL post-allogeneic BMT by PCR. The early attainment of molecular remission in the absence of GVHD suggests that the conditioning regimen may have been more important than a graft-versus-leukaemia effect in these patients. Follow-up of larger numbers of patients will be required to confirm these preliminary observations. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the effect of autologous stem cell transplantation (SCT) conditioned by BEAM chemotheraphy for patients that suffer from Waldenström's macroglobulinaemia and lymphoplasmacytic lymphoma.

Persistence of disease after salvage therapy among relapsed or refractory Hodgkin lymphoma (HL) patients predicts poor outcome. Here, we report on 41 HL patients with active disease after salvage therapy and who received high-dose melphalan (HD-PAM) and auto-SCT as a bridge to a second autologous or an allogeneic transplantation between 2002 and 2013 at our center. Disease response was based on 18-fluoro-deoxyglucose-positron emission tomography results in all patients. Overall response rate after HD-PAM was 78% and it did not differ among PR or stable/progressive disease patients (P=1.00). Response was associated with better OS: hazard ratio=0.32 (95% confidence interval: 0.13-0.77, P=0.01) irrespective of disease status before HD-PAM. Thirty-three patients (80%) were able to complete the planned treatment, intended as tandem autologous or auto-allo transplant. Hematological and extrahematological toxicity of HD-PAM was manageable, without any treatment-related death. In conclusion, HD-PAM is a valuable therapeutic option in relapsed/refractory HL patients with active disease after salvage therapy, with an impressive 78% overall response rate and 80% rate of proceeding to further transplantation. The present data may be integrated with the growing literature on new drugs in the field of relapsed/refractory HL. [ABSTRACT FROM AUTHOR]

DLI is traditionally used to provide graft-versus-leukemia (GvL) effects when given to patients relapsing post-hematopoietic cell transplantation (HCT). However, it is often associated with significant GvHD and has only modest efficacy against acute leukemias. Therefore, novel cellular therapies are needed to improve the outcome of high-risk or relapsed leukemia patients following HCT. Activated T helper-1 (aTh-1) lymphocytes are CD4+CD25+CD40L+CD62Llo effector memory cells that produce large amounts of IFN-γ and TNF-α. We demonstrate that post-transplant adoptive aTh-1 cell therapy enhances GvL with limited GvHD in an MHC-mismatched murine BMT model. aTh-1 infusions result in superior leukemia-free survival when compared with unstimulated splenocytes (SC), purified CD4+ T-cells and T-cell-enriched SC. aTh-1 cells display cytotoxicity against A20 leukemia cells in vitro and persist in vivo for at least 2 months following adoptive transfer. Furthermore, in contrast to unstimulated SC, aTh-1 cell infusion is associated with only transient, mild suppression of donor-derived hematopoiesis. aTh-1 cell therapy is safe, effective and warrants further investigation as an alternative to DLI. [ABSTRACT FROM AUTHOR]

Modern treatment strategies have increased life expectancy in multiple myeloma, but little is known about the endocrine, metabolic and nutritional status of long-term survivors. We performed endocrine, metabolic, bone, body composition and nutritional evaluations in 32 patients with intensively-treated, advanced but stable, myeloma a median duration of 6 years from diagnosis and three lines of intensive treatment, including at least one haematopoietic SCT procedure. All patients were off active treatment. There was a high prevalence of endocrine dysfunction: hypothyroidism (9%), hypogonadism (65% males) and elevated prolactin (19%). Adrenocortical function was preserved despite large cumulative corticosteroid pretreatment. Biochemical markers were consistent with postmenopausal status in all females and infertility in males. Nutritionally, 59% were vitamin D insufficient/deficient, reduced serum folate in 25% and vitamin B12 in 6%. Total body DEXA scanning confirmed 'sarcopenic-obesity' in 65%, but reduced bone density was seen in a minority. We conclude that potentially correctable endocrine, metabolic and nutritional abnormalities are prevalent in heavily-treated patients with stable multiple myeloma. Preservation of bone supports the efficacy of bisphosphonate treatment from diagnosis, but sarcopenic-obesity may contribute to frailty. Ultimately, multi-system screening and appropriate interventions may optimise quality of long-term survival and further studies are warranted. [ABSTRACT FROM AUTHOR]

Despite the undoubted improvement in the prognosis of patients with diffuse large B-cell lymphomas (DLBCLs) with the addition of rituximab in the front-line treatment, a significant proportion of patients still relapse. Salvage immune-chemotherapy followed by high-dose therapy with autologous haematopoietic cell transplantation (auto-HCT) remains the treatment of choice for such patients, especially in those who demonstrate chemosensitive disease. In recent years, allogeneic haematopoietic cell transplantation (allo-HCT) has increasingly been used for patients who are resistant to salvage treatment or relapse after an auto-HCT. Strategies using reduced intensity conditioning regimens have allowed application of this approach to a broader range of patients. PFS is up to 55% with a risk of relapse up to 80% depending on different studies. In multivariate analysis, several factors have been associated with favourable outcome including chemosensitivity of the disease, younger age and Karnofsky performance status at the time of the transplant being the strongest ones. DLIs have shown to induce durable responses in relapsed or progressed disease; however, its role remains controversial as the results are inferior to the responses seen in other haematological malignancies. More recently, the addition of MoAbs in the non-myeloablative conditioning regimens has shown encouraging results. In conclusion, allo-HCT is a feasible option in selective patients with chemosensitive DBCL, as it reduces the risk of relapse; however, this is achieved at the cost of significant non-relapse mortality. [ABSTRACT FROM AUTHOR]

Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0-14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5-15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II-III (28%), viral reactivation (16%), thrombocytopenia (III-IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18-66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28-76) and 79% (95% CI: 63-95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered. [ABSTRACT FROM AUTHOR]

We evaluated immune reconstitution in 58 adults who received hematopoietic SCTs from allogeneic siblings (allosib), matched unrelated donors (MUD) or cord blood (CB) at 90-day intervals for 1 year post transplant. CB recipients had a higher incidence of infections in the first 100 days compared with allosib and MUD recipients. The number of circulating T cells was lower in CB recipients compared with MUD recipients at 90 days and compared with allosib recipients at 180 days. Spectratype analysis of the TCR Vβ complementarity determining region 3 (CDR3) of patient lymphocytes revealed that the TCR repertoire remained poorly diversified even at 360 days in nearly all patients. In contrast, the number of circulating B cells was significantly elevated in CB recipients compared with allosib recipients throughout the first year post transplant and compared with MUD recipients at 9-12 months. Spectratype analysis of the B-cell receptor VH CDR3 showed that the B-cell repertoire was diversified in most patients by 90 days. CD5pos B cells from assayed CB recipients expressed intracellular IL-10 early post transplant. Our data suggest that B cells, in addition to T cells, may have a role in impaired immune responses in CB transplant patients. [ABSTRACT FROM AUTHOR]

Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P=0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivation-more frequent in alemtuzumab recipients-was associated with paraproteinaemia (HR 7.52, P<0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P=0.048) and CMV reactivation (HR 5.74, P=0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P=0.04) and relapse increased (HR 2.38, P=0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS. [ABSTRACT FROM AUTHOR]

There exists a need for effective salvage regimens for multiple myeloma patients being considered for reduced-intensity allogeneic hematopoietic SCT (RI-alloHSCT). We developed EPOCH-F, a regimen consisting of infusional etoposide, VCR and adriamycin with prednisone, CY and fludarabine to achieve both tumor control and host lymphocyte depletion to facilitate engraftment before RI-alloHSCT. In all, 22 multiple myeloma patients were treated with EPOCH-F before RI-alloHSCT. The median age was 53 years (range 36-65), and the median number of previous therapies was 2 (range 1-8). Patients received a median of three cycles (range 1-5) of EPOCH-F. Toxicities were primarily hematologic and manageable. Median lymphocyte counts decreased from 1423/μL (range 335-2788) to 519/μL (range 102-1420; P=0.0002). The overall response (PR) to EPOCH-F was 22 with 13% achieving a CR/near-complete response (nCR); only 1 patient progressed while on therapy. A total of 20 patients underwent RI-alloHSCT. Median day +100 donor chimerism was 100% (range 60-100). In all, 70% of patients achieved very good partial response or better response after transplant; 40% of patients achieved CR/nCR. TRM at 100 days and 5 years was 5 and 30%, respectively. Median OS after RI-alloHSCT was 46.1 months. EPOCH-F provides disease control and host lymphocyte depletion with consistent full donor engraftment in multiple myeloma patients undergoing RI-alloHSCT. [ABSTRACT FROM AUTHOR]

By retrospective analysis of 88 patients from the British Society of Blood and Marrow Transplantation registry, we investigated the effect of in vivo T-cell depletion in HLA-identical sibling reduced-intensity conditioning (RIC) allografts for adult AML by comparing patients who received alemtuzumab with those without alemtuzumab conditioning. Both groups were equivalent for age, sex, karyotype and disease status at transplant. With a median follow-up of 27 months (3–72 months) and 48 months (7–72 months), the 2- and 5-year overall survival, with or without alemtuzumab, is 60 and 60% (P=0.80) and 61 and 53%, respectively (P=0.85). The 2-year non-relapse mortality is 12% with alemtuzumab, and 17% without alemtuzumab (P=0.49). The 2-year relapse rate is 35% with alemtuzumab compared with 19% without alemtuzumab (P=0.28). Grades II–IV acute GVHD occurred in 22% (8/37) without alemtuzumab compared with 14% (7/51) given alemtuzumab (P=0.25). Extensive chronic GVHD occurred in 47% (14/30) not given alemtuzumab compared with 4% (2/45) who were given alemtuzumab (P=0.001). Among evaluable patients, the risk of infections was higher in those treated with alemtuzumab compared with those not treated with alemtuzumab (79 vs 57%, respectively, P=0.02). In conclusion, alemtuzumab has a beneficial effect by reducing chronic GVHD without affecting overall survival. Further studies are warranted before alemtuzumab can be recommended as standard in RIC allografts for AML.Bone Marrow Transplantation (2009) 43, 709–715; doi:10.1038/bmt.2008.375; published online 24 November 2008 [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusions (DLI) often are used after allo-SCT to augment the graft-versus-tumor effect. Timing of infusion varies according to indication, for example to treat tumor recurrence, as a planned strategy to prevent disease relapse in the setting of T-cell-depleted grafts or non-myeloablative conditioning regimens, or as a method to convert mixed to full donor chimerism. The optimal strategy of timing, use of cytotoxic conditioning, cell dose and cell product composition, and so on, for DLI administration remains unclear. Despite varied techniques, DLI may lead to 3-year disease-free survivals (DFS) in excess of 60% for all CML patients and approach 90% in patients with only molecular or cytogenetic relapse. Other hematologic malignancies appear much less responsive, as less than 50% of patients respond and provide, at best, 3-year DFS rates of 20–50%. Multiple myeloma patients have overall response rates of 40–45% after DLI, suggesting benefit in relapsed disease, but limited experiences for diseases such as Hodgkin's lymphoma, myelodysplasia and ALL preclude recommendations for use of DLI at this time. Regardless of the indication, treatment-related mortality after DLI is 5–20% and more than one-third of patients will develop acute and/or chronic GVHD after DLI. The risks of these complications appear related, in part, to donor source, cell dose and therapy prior to DLI. Although there are no definitive answers, the information gleaned from published literature suggests that DLI should be administered early after relapse or as a prophylactic strategy in patients receiving T-cell-depleted grafts, and patients with bulky or aggressive disease may benefit from disease reduction prior to DLI.Bone Marrow Transplantation (2008) 42, 569–579; doi:10.1038/bmt.2008.259; published online 18 August 2008 [ABSTRACT FROM AUTHOR]

The place of allogeneic SCT in the management of multiple myeloma remains controversial. Although it may induce long-term clinical and molecular remissions, the very high transplant-related toxicity after a myeloablative preparative regimen has limited its role to younger patients as first-line treatment option. Even with this limited indication, toxic death rate related to infections and GVHD is considered too high and this strategy has been almost abandoned. Reduced intensity conditioning (RIC) regimens look promising, as the transplant-related mortality is low even with matched unrelated donors and can be considered for older patients up to the age of 65 years. However when used in patients with a high tumor burden or with chemo-resistant disease, the immunologic effect of the graft is not sufficient to avoid relapses. Therefore, RIC allotransplantation is currently used after tumor mass reduction with high-dose therapy followed by autologous SCT. A recently published Italian study shows that this strategy induces better event-free survival than double autologous SCT due to a reduced relapse rate. The questions raised by this encouraging result are discussed in this paper.Bone Marrow Transplantation (2007) 40, 1123–1128; doi:10.1038/sj.bmt.1705810; published online 6 August 2007 [ABSTRACT FROM AUTHOR]

The presence of clonal gammopathies (CG) has been reported following both conventional myeloablative and autologous haematopoietic stem cell transplantation (HSCT). We monitored the occurrence of CG in a cohort of patients with myeloid malignancies receiving FBC (fludarabine-busulphan-alemtuzumab)-based reduced intensity conditioned (RIC) HSCT, and assessed its correlation with infections, graft-versus-host disease (GvHD) and survival. Serial serum protein electrophoresis was analysed in a total of 138 patients and CG were detected in 49 patients (36%). The predominant Ig isotype was IgG (82%). There was no difference in the incidence of viral infections between patient groups. However, patients with gammopathies were more likely to have had prior chronic GvHD (OR 2.7, 95% CI 1.3–5.5, P<0.001). On multivariate analysis, the only factors that were found to influence overall survival (OS) were presence of gammopathies, which was associated with an improved OS (OR 0.35 95% CI 0.14–0.86, P=0.02) as well as disease stage, patients with advanced disease having a higher risk of death (OR 2.20 95% CI 1.18–4.11, P=0.02). Disease stage was the only variable that influenced relapse incidence on multivariate analysis (OR 4.22 95% CI 1.82–9.78, P<0.01). Clonal gammopathies are a frequent but benign occurrence following alemtuzumab-based RIC HSCT, and their appearance may define a group of patients with a favourable overall outcome.Bone Marrow Transplantation (2007) 40, 747–752; doi:10.1038/sj.bmt.1705805; published online 20 August 2007 [ABSTRACT FROM AUTHOR]

Advances in the past few years have significantly improved adoptive immunotherapy strategies available following autologous and allogeneic hematopoietic stem cell transplantation (HSCT). Minimal residual disease, relapsed disease and viral infections remain a significant cause of mortality in patients undergoing HSCT. Novel therapies are critically needed to overcome these management dilemmas, while sparing the graft-versus-tumor effect and avoiding graft-versus-host disease. This review focuses on the T-cell strategies currently available to allay disease while minimizing toxicities in patients who have undergone HSCT.Bone Marrow Transplantation (2007) 40, 93–104; doi:10.1038/sj.bmt.1705667; published online 14 May 2007 [ABSTRACT FROM AUTHOR]

Summary:Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48?mg; days-21 to-19), fludarabine (150?mg/m2; days-8 to-4), melphalan (140/70?mg/m2; day-3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5×109/l) and platelets (>50×109/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78-907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1-2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.Bone Marrow Transplantation (2005) 35, 345-352. doi:10.1038/sj.bmt.1704795 Published online 13 December 2004 [ABSTRACT FROM AUTHOR]

Summary:During follow-up after allogeneic stem cell transplantation (SCT), patients frequently lose their immunity to infectious agents such as measles. The aim of this study was to analyze the influence of different factors on measles immunity. In total, 395 patients with a disease-free survival of at least 1 year were included. Measles vaccination was given at 2 years after SCT to children and young adults without chronic GVHD or ongoing immunosuppression. In all, 264 patients had matched sibling donors and 131 either mismatched family or unrelated donors. Totally, 318 patients received bone marrow and 77 peripheral blood stem cells. Overall, 375 patients had undergone myeloablative and 20 nonmyeloablative conditioning. Out of 395 patients, 133 (34%) were seronegative to measles. In multivariate models, younger age or being vaccinated to measles, rather than previous measles disease, before transplantation were risk factors both for becoming seronegative and to have doubtfully protective immunity to measles. Acute GVHD grade II-IV was a risk factor for seronegativity and blood stem cells a risk factor for doubtfully protective immunity. Children and young adults previously immunized to measles have a high risk for becoming vulnerable to a measles infection. Since measles is again circulating in many countries and measles is a serious infection after SCT, vaccination should be considered.Bone Marrow Transplantation (2004) 34, 589-593. doi:10.1038/sj.bmt.1704634 Published online 9 August 2004 [ABSTRACT FROM AUTHOR]

Presents an index of authors of articles on bone marrow transplantation.