Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on ...European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.
Summary
What is known and objective
Ibrutinib is a recently approved oral anticancer agent with pharmacokinetics that is very sensitive to metabolic inhibition. We report a serious side effect of ...ibrutinib potentially attributable to interaction with the moderate CYP3A4 inhibitor verapamil.
Case description
A patient with mantle cell lymphoma was admitted to our emergency department with severe diarrhoea. During a prescription review, the clinical pharmacist identified a potential drug interaction between ibrutinib and verapamil present in a branded combination product also containing trandolapril. Ibrutinib was discontinued for 5 days, and verapamil was stopped. Lercanidipine 10 mg daily was prescribed as an alternative antihypertensive drug. The patient was discharged after 3 days with symptomatic treatment for his diarrhoea. Three months later, the patient maintained control with ibrutinib and olmesartan, but without verapamil.
What is new and conclusion
This is the first description of a serious side effect of ibrutinib likely due to an interaction with the CYP3A4 inhibitor verapamil. Prescriptions of ibrutinib must be carefully checked to identify possible interactions with CYP3A4 inhibitors and patients monitored accordingly.
Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on ...transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia.
Hematopoietic stem cell transplantation (HSCT) for severe ADs was developed over the past 25years and is now validated by national and international medical societies for severe early systemic ...sclerosis (SSc) and relapsing-remitting multiple sclerosis (MS) and available as part of routine care in accredited center. HSCT is also recommended, with varying levels of evidence, as an alternative treatment for several ADs, when refractory to conventional therapy, including specific cases of connective tissue diseases or vasculitis, inflammatory neurological diseases, and more rarely severe refractory Crohn's disease. The aim of this document was to provide guidelines for the current indications, procedures and follow-up of HSCT in ADs. Patient safety considerations are central to guidance on patient selection and conditioning, always validated at the national MATHEC multidisciplinary team meeting (MDTM) based on recent (less than 3months) thorough patient evaluation. HSCT procedural aspects and follow-up are then carried out within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and SFGM-TC accredited centres in close collaboration with the ADs specialist. These French recommendations were performed according to HAS/FAI2R standard operating procedures and coordinated by the Île-de-France MATHEC Reference Centre for Rare Systemic Autoimmune Diseases (CRMR MATHEC) within the Filière FAI2R and in association with the Filière MaRIH. The task force consisted of 3 patients and 64 clinical experts from various specialties and French centres. These data-derived and consensus-derived recommendations will help clinicians to propose HSCT for their severe ADs patients in an evidence-based way. These recommendations also give directions for future clinical research in this area. These recommendations will be updated according to newly emerging data. Of note, other cell therapies that have not yet been approved for clinical practice or are the subject of ongoing clinical research will not be addressed in this document.
La greffe de cellules souches hématopoïétiques (GCSH) pour les maladies auto-immunes (MAI) sévères s’est développée au cours des 25 dernières années et est maintenant validée par les sociétés savantes nationales et internationales pour la sclérodermie systémique sévère précoce et la sclérose en plaques récurrente-rémittente et est disponible dans le cadre des soins courants dans des centres accrédités. La GCSH est également recommandée, avec des niveaux de preuve variables, comme traitement alternatif pour plusieurs MAI, lorsqu’elles sont réfractaires aux thérapies conventionnelles, comprenant des cas spécifiques de connectivites ou de vascularites ; des maladies neuro-inflammatoires ; et plus rarement les maladies de Crohn réfractaires sévères. L’objectif de ce document est de fournir des recommandations sur les indications actuelles, les procédures et le suivi de la GCSH dans les MAI. La sécurité des patients reste l’élément majeur guidant la sélection et le conditionnement des patients, toujours validées lors de la réunion de concertation pluridisciplinaire nationale MATHEC sur la base d’une évaluation exhaustive et récente (moins de 3 mois) du patient. La GCSH et le suivi sont ensuite effectués dans des centres expérimentés et accrédités par le Joint Accreditation Committee of International Society for Cellular Therapy et la SFGM-TC, en étroite collaboration avec le spécialiste des MAI. Ces recommandations françaises ont été réalisées conformément aux procédures opérationnelles standard de la HAS/FAI2R et coordonnées par le Centre de référence des maladies auto-immunes systémiques rares d’Île-de-France MATHEC (CRMR MATHEC) au sein de la Filière FAI2R et en association avec la Filière MaRIH. Le groupe de travail était composé de 3 patients et de 64 cliniciens experts issus de différentes spécialités et de différents centres français. Ces recommandations issues des données publiées et de consensus d’experts aideront les cliniciens à proposer la GCSH à leurs patients atteints de MAI sévère. Ces recommandations ouvrent également des perspectives de recherche clinique. Ces recommandations seront régulièrement mises à jour en fonction des nouvelles données publiées. Il convient de noter que les autres thérapies cellulaires qui n’ont pas encore été approuvées par les autorités de santé ou qui font l’objet d’essais cliniques en cours ne seront pas abordées dans ce document.
High-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in ...female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation.
Between 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15–48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%).
Nine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm−), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1–219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm− following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3–219 months).
Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.
This retrospective analysis compared two regimens of fludarabine combined with i.v. BU 6.4 mg/kg (FB2) or BU 12.8 mg/kg (FB4) for allografting of AML in first CR. A total of 437 patients (median age: ...50 years) were administered FB2 (n = 225, 51%) or FB4 (n = 212, 49%). Median follow-up time was 28 months. Use of FB2 resulted in a longer time to neutrophil engraftment (17 vs 15 days, P < 0.0001) but no difference in incidence of grade II-IV acute (P = 0.54) or chronic GVHD (P = 0.51). In patients < 50 years of age, FB2 was associated with a higher 2-year cumulative incidence of relapse (33 ± 6% vs 20 ± 4%, P = 0.04), but there was no difference in 2-year leukemia-free survival (LFS) (P = 0.45), OS (P = 0.53) or non-relapse mortality (P = 0.17). In recipients ⩾ 50 years of age, FB2 resulted in better 2-year LFS (63 ± 4% vs 42 ± 7%, P = 0.02) and OS (68 ± 4% vs 45 ± 7%, P = 0.006); a lower 2-year non-relapse mortality, albeit not statistically significant (15 ± 3% vs 29 ± 6%, P = 0.06), was observed with FB2. FB2 is an effective and well-tolerated regimen in patients ⩾ 50 years of age and does not compromise survival when used in patients <50 years undergoing allogeneic transplantation for AML in first CR.
We prospectively evaluated the safety and efficacy of a clofarabine, intravenous busulfan and antithymocyte globulin-based reduced-toxicity conditioning (CloB2A2) regimen before allogeneic stem cell ...transplantation. Thirty high-risk patients (median age: 59 years; acute myeloid leukemia n=11, acute lymphoblastic leukemia n=13; myelodysplastic syndrome n=5, bi-phenotypic leukemia n=1) were included in this phase 2 study. At time of their transplant, 20 and seven patients were in first and second complete remission, respectively, while three patients with myelodysplastic syndrome were responding to chemotherapy or who had not been previously treated. The CloB2A2 regimen consisted of clofarabine 30 mg/m(2)/day for 4 days, busulfan 3.2 mg/kg/day for 2 days and antithymocyte globulin 2.5 mg/kg/day for 2 days. The median follow-up was 23 months. Engraftment occurred in all patients. The 1-year overall survival, leukemia-free survival, relapse incidence and non-relapse mortality rates were 63±9%, 57±9%, 40±9%, and 3.3±3%, respectively. Comparing patients with acute myeloid leukemia/myelodysplastic syndrome versus those with acute lymphoblastic leukemia/bi-phenotypic leukemia, the 1-year overall and leukemia-free survival rates were 75±10% versus 50±13%, respectively (P=0.07) and 69±12% versus 43±13%, respectively (P=0.08), while the 1-year relapse incidence was 25±11% versus 57±14%, respectively (P=0.05). The CloB2A2 regimen prior to allogeneic stem cell transplantation is feasible, allowing for full engraftment and low toxicity. Disease control appears to be satisfactory, especially in patients with acute myeloid leukemia/myelodysplastic syndrome. The trial was registered at www.clinicaltrials.gov no. NCT00863148.
Allogeneic hematopoietic SCT (HSCT) has been used as treatment for single patients with autoimmune diseases (AD). To summarise currently available information, we analyzed all patients who underwent ...allogeneic HSCT for AD and who reported to the European Group for Blood and Marrow Transplantation (EBMT) database. Thirty-five patients receiving 38 allogeneic transplantations for various hematological and non-hematological AD were identified. Four patients had had an allogeneic HSCT for a conventional hematological indication in the past. Fifty-five per cent of the transplantation procedures led to a complete clinical response of the refractory AD and 23% to at least a partial response. The median duration of response at the last follow-up was 70.7 (15.2-130) months. Three patients relapsed at a median of 12.3 months after HSCT. Treatment-related mortality at 2 years was 22.1% (95% CI: 7.3-36.9%). Two deaths were caused by progression of AD. The probability of survival at 2 years was 70%. No single factor predicting the outcome could be identified. The retrospective nature of this study and the heterogeneous, partly incomplete data are its limitations. However, allogeneic HSCT can induce remission in patients suffering from refractory AD. These data provide the basis for carefully conducted prospective trials.
Allogeneic hematopoietic transplantation is increasingly used in patients aged 55 years or more with AML. The question of whether outcomes can be improved with an allele-level 8/8 HLA-matched ...unrelated donor (MUD) rather than an older HLA-matched sibling (MSD, more than 55 years) is still unanswered. We thus analyzed outcomes in 714 patients aged 55 years and older with AML in first CR (CR1) who received PBSCs after a reduced-intensity conditioning hematopoietic cell transplant from a MUD (n=310) or a MSD (n=404) in a recent period (2005-2010). The 3-year cumulative incidences (CIs) of non-relapse mortality were 17% and 23% with MSD and MUD, respectively (P=0.17). The 3-year CIs of relapse were 37% and 30%, respectively (P=0.12), resulting in a 3-year CI of leukemia-free survival of 46% and 47%, respectively (P=0.51). The 3-year overall survival was 49% with both MSD and MUD. In conclusion, HLA-identical sibling donors aged 55 years or more should not be excluded because of age for patients aged 55 years and older with AML in CR1.
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