Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome.

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides and Sézary syndrome. An updated experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option in advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS). This study presents an updated analysis of the initial experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) describing the outcomes after allo-HSCT for MF and SS, with special emphasis on the impact of the use of unrelated donors (URD). METHODS AND PATIENTS: Eligible for this study were patients with advanced-stage MF or SS who underwent a first allo-HSCT from matched HLA-identical related or URD between January/1997 and December/2011. Sixty patients have been previously reported. RESULTS: 113 patients were included [77 MF (68%)]; 61 (54%) were in complete or partial remission, 86 (76%) received reduced-intensity protocols and 44 (39%) an URD allo-HSCT. With a median follow up for surviving patients of 73 months, allo-HSCT resulted in an estimated overall survival (OS) of 38% at 5 years, and a progression-free survival (PFS) of 26% at 5 years. Multivariate analysis demonstrated that advanced-phase disease (complete remission/partial remission >3, primary refractory or relapse/progression in patients that had received 3 or more lines of systemic treatment prior to transplant or the number of treatment lines was not known), a short interval between diagnosis and transplant (<18 months) were independent adverse prognostic factors for PFS; advanced-phase disease and the use of URDs were independent adverse prognostic factors for OS. CONCLUSIONS: This extended series supports that allo-HSCT is able to effectively rescue over one third of the population of patients with advanced-stage MF/SS. High relapse rate is still the major cause of failure and needs to be improved with better strategies before and after transplant. The negative impact of URD is a matter of concern and needs to be further elucidated in future studies.

Three distinct hematological malignancies from a single germ cell tumor: a case report.

BACKGROUND: The association between non seminomatous germ cell tumors (GCTs) and hematological malignancies of rare lineage has been described in the literature. In some of these cases there is evidence that the leukemia derives from a pluripotent primitive clone present in the original germ cell tumor. CASE PRESENTATION: We present a highly unusual case of a 23-year-old man of South Asian origin with a history of Klinefelter's syndrome who initially developed mediastinal non seminomatous GCT. Following treatment with surgery and standard chemotherapy he went on to develop three different hematological malignancies of distinct lineages in sequential fashion over a short time period. Despite treatment with multiple intensive chemotherapy regimens and a matched unrelated donor allogeneic stem cell transplant, he died 41 months after initial diagnosis of his GCT and 10 months after the first diagnosis of hematological malignancy. CONCLUSIONS: This is an extreme case that highlights the pluripotency and aggressiveness of these GCT-derived hematological malignancies, and the need for novel therapeutic approaches.

Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation.

Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient's weight. One fraction was used for the first transplant after median storage of 60 days (range, 17-165) and another fraction was used after median storage of 1448 days (range, 849-3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11-21) after the first and 13 days (10-20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.

Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.

The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.

Antifungal prophylaxis with anidulafungin to minimize drug interactions with an antiepileptic treatment in a hematopoietic stem cell transplant recipient.

WHAT IS KNOWN AND OBJECTIVE: Invasive fungal infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). This provides a clear rationale for antifungal prophylaxis in this population. A concern is the potential for drug interactions, given that most of antifungals are metabolized through the P450 cytochrome system. CASE SUMMARY: We present a case of a 33-year-old woman, with a past history of high-risk epilepsy, who underwent allogeneic HSCT for a myelodysplastic syndrome. Anidulafungin was successfully used as antifungal prophylaxis to minimize drug interactions with her antiepileptic treatment. WHAT IS NEW AND CONCLUSION: This is the first reported case of antifungal prophylaxis with this echinocandin in HSCT. Anidulafungin may be an option in transplant recipients with multiple risk factors for drug interactions.

Viral-specific adoptive immunotherapy after allo-SCT: the role of multimer-based selection strategies.

Recipients of hematopoietic SCT undergo a period of profound immunosuppression due to the chemotherapy and/or radiotherapy used for the conditioning and to the graft versus host reaction. SCT patients are highly susceptible to the development of viral infections such as CMV or EBV. The achievement of a competent immunological response, such as viral-specific T cells, is associated with a lower incidence of viral infections. Methods for direct identification of antigen-specific T cells have been based on the functional characteristics of these T cells. Techniques such as proliferation and ELISPOT assays, intracellular cytokine staining and IFN-γ capture have been used to quantitate and obtain viral-specific T cells. Multimers are composed of several MHC molecules loaded with immunodominant peptides joined to a fluorescent molecule, which signal can be quantified by a flow cytometer. Multimer technology together with recent advances in flow cytometry, have facilitated the monitoring and selection of antigen-specific T cells without the need for in vitro cultures and manipulation. This has resulted in a better characterization of the function and phenotype of the different subpopulations of T cells involved in the immune recovery post allogeneic SCT. It is becoming a distinct possibility to isolate individual antigen-specific T cells, without long-term culture techniques, and potentially use them as adoptive immunotherapy in the SCT setting.

Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation.

Peripheral blood used as a source of stem cells for transplantation (PBSCT) is known to exert stronger immune-mediated effects compared with BM (BMT). We decided to retrospectively analyze the impact of stem cell source on the OS of CML patients who relapsed after either matched related donor PBSCT (N=168) or BMT (N=216) and were treated with donor lymphocyte infusions (DLI). Univariate analysis revealed a lower probability of OS after DLI in patients relapsing after PBSCT vs BMT (66% vs 79% at 5 years, P=0.013). However, a multivariate Cox analysis did not reveal any significant impact of PBSCT as a risk factor for decreased OS for patients transplanted in first chronic phase (CP1; hazard ratio (HR) 1.036, 95% confidence interval (CI) 0.619-1.734). A statistical interaction term suggested that the impact of stem cell source on OS after DLI was different for those transplanted in advanced phases (negative impact of previous PBSCT-HR 2.176, 95% CI 0.930-5.091). In summary, the stem cell source does not affect the OS of CML patients who underwent PBSCT in CP1, relapsed and were treated with DLI. However, when the patients were transplanted in advanced phases, previous PBSCT seems to negatively affect OS after DLI compared with BMT.

Sign of the Zodiac as a predictor of survival for recipients of an allogeneic stem cell transplant for chronic myeloid leukaemia (CML): an artificial association.

BACKGROUND: Astrological or Zodiac (star) sign has been shown to be a statistically significant factor in the outcome of a variety of diseases, conditions, and phenomena. METHODS: To investigate its relevance in the context of a stem cell transplant (SCT), we examined its influence in chronic myeloid leukaemia, a disease with well-established prognostic factors. Data were collected on 626 patients who received a first myeloablative allogeneic SCT between 1981 and 2006. Star sign was determined for each patient. RESULTS: Univariate analyses comparing all 12 individual star signs showed considerable variation of 5-year probabilities of survival, 63% for Arians, to 45% for Aquarians, but without significance (P=.65). However, it was possible to pool together star signs likely to provide dichotomous results. Thus, grouping together Aries, Taurus, Gemini, Leo, Scorpio, and Capricorn (group A; n=317) versus others (group B; n=309) resulted in a highly significant difference (58% vs 48%; P=.007). When adjusted for known prognostic factors in a multivariate analysis, group B was associated with an increased risk of mortality when compared with group A (relative risk [RR], 1.37; P=.005). CONCLUSION: In this study, we show that, providing adequate care is taken, a significant relationship between patient star sign and survival post SCT for CML can be observed. This is, however, a completely erroneous result, and is based on the pooling together of observations to artificially create a statistically significant result. Statistical analyses should thus be carried out on a priori hypotheses and not to find a meaningful or significant result.

Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the Chronic Leukemia Working Party of the EBMT.

We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (< or =45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.

Remisión molecular de una leucemia mieloide crónica en un paciente con segundo trasplante renaly hepatitis / No disponible

La leucemia mieloide crónica (LMC) es una enfermedad mieloproliferativa caracterizada por la expansión clonal de células mieloides que expresan la proteína de fusión BCR-ABL, responsable de los efectos oncogénicos de la LMC. La terapia actual en el tratamiento de LMC es el inhibidor de la BCR-ABL tirosín-kinasa, imatinib. Aunque este fármaco ha demostrado mejorar la supervivencia en pacientes con LMC, su papel en el contexto del trasplante renal no ha sido ampliamente descrito en la literatura. Presentamos un caso de remisión molecular de LMC en un varón de 55 años con un segundo trasplante renal, hepatitis C y con riesgos cardiovascularese inmunológicos asociados (AU)

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of cells in the myeloid line, expressing the BCRABL fusion protein responsible for the oncogenic effect of CML. The current frontline therapy in CML is the BCR-ABL tyrosine kinase inhibitor, Imatinib. Although this drug has been shown to improve survival in CML patients, its role in the context of a transplant setting has not been widely described in the literature. We report on the long termmolecular remission of CML in a 55 year old man with a second renal transplant who is hepatitis C virus positive,and has associated cardiovascular and immunological riskfactors (AU)

[Molecular remission of chronic myeloid leukaemia in a patient with hepatitis and a second kidney transplant]. / Remisión molecular de una leucemia mieloide crónica en un paciente con segundo trasplante renal y hepatitis.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of cells in the myeloid line, expressing the BCR-ABL fusion protein responsible for the oncogenic effect of CML. The current frontline therapy in CML is the BCR-ABL tyrosine kinase inhibitor, Imatinib. Although this drug has been shown to improve survival in CML patients, its role in the context of a transplant setting has not been widely described in the literature. We report on the long term molecular remission of CML in a 55 year old man with a second renal transplant who is hepatitis C virus positive, and has associated cardiovascular and immunological risk factors.

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML.

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.

The harvest and use of autologous back-up grafts for graft failure or severe GVHD after allogeneic hematopoietic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation.

Autologous hematopoietic stem cells (HSCs) harvested as back-up prior to allogeneic hematopoietic SCT (HSCT) may potentially be useful in the treatment of graft failure or in cases with severe GVHD. Here, we studied the general policies and indications for autologous back-up harvest among the European Group for Blood and Marrow Transplantation centers in the year 2003. The outcome of patients receiving autologous back-up transfusion between 1998 and 2002 was evaluated retrospectively. The responses from 94 centers showed that 48 centers had a general policy with variable indications for autologous back-up harvest. Thirty-five patients with graft failure (25), GVHD (8) or relapse (2) retransplanted with autologous back-ups were reported. Autologous back-up transfusion was performed at a median of 35 days (patients with graft failure) or 90 days (patients with GVHD) after allogeneic HSCT. Within 100 days after autologous HSCT, 21 patients died from treatment-related complications (19) or relapse (2). Estimated overall survival at 1 year was 16% (95% CI 0-32%) for patients treated for graft failure and 13% (95% CI 0-37%) for GVHD patients. In conclusion, our data demonstrate that the indication for autologous back-up harvests is limited and that general storage and use cannot be recommended unless in selected prospective studies.

Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy.

Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell dose < or =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.

LACE-conditioned autologous stem cell transplantation for relapsed or refractory Hodgkin's lymphoma: treatment outcome and risk factor analysis in 67 patients from a single centre.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed Hodgkin's lymphoma. We have analysed 67 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n=61) or primary refractory (n=6) Hodgkin's lymphoma. The 100-day treatment-related mortality was 3%. With a median follow-up of 67 months (range 3.3-161.0) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 68 and 64%, respectively. Probabilities for OS and PFS at 5 years for patients with chemosensitive relapse (n=40) were 81 and 78% versus 50 and 35%, respectively, for patients (n=27) with chemoresistant relapse (P=0.012 for OS, P=0.002 for PFS). In multivariate analysis mixed cellularity classical or lymphocyte-depleted classical histology subtype and haemoglobin level of 10 g/dl or less at the time of ASCT were identified as risk factors for worse OS, whereas stage III or IV disease at diagnosis and disease status at ASCT other than complete or partial remission predicted inferior PFS. LACE followed by ASCT is an effective treatment for the majority of patients with chemosensitive relapsed Hodgkin's lymphoma and a proportion of chemorefractory patients also benefit.

Predictive factors for survival in myeloma patients who undergo autologous stem cell transplantation: a single-centre experience in 211 patients.

High-dose therapy with autologous stem cell therapy (ASCT) has become the treatment of choice for eligible patients with myeloma. We analysed retrospectively the prognostic influence of pre-transplant characteristics and transplant modalities on response and survival in 211 myeloma patients who were transplanted in our centre between 1994 and 2004. All patients received peripheral blood stem cell support after conditioning with melphalan alone (183 patients), or melphalan and total blood irradiation (28 patients). We evaluated the influence of age, type of multiple myeloma, status prior and post ASCT, previous treatment regimens, time of ASCT from diagnosis, year of autograft, dose of re-infused CD34(+) cells, plasma cell infiltration and beta2-microglobulin at diagnosis on overall survival (OS) and event-free survival (EFS) to define patients with better prognosis. Median OS and EFS from transplantation were 50.9 and 20.1 months, respectively. Median OS from diagnosis was 68.8 months. Transplant-related mortality was 1.4%. Lower beta2-microglobulin levels, achievement of complete remission (CR) post transplant and lower plasma cell infiltration at diagnosis and transplant correlated with longer EFS and OS, whereas CR at transplant and low international prognostic index at transplant correlated with better EFS. Higher CD34(+) cell dose correlated with improved OS. We conclude that ASCT is safe and effective and the outcome is independent of age, time from diagnosis, previous treatment and conditioning regimen.

Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse.

We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of 'residual' disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.