[Severe systemic vasculitis induced by ibrutinib]. / Vascularite systémique sévère induite par l'ibrutinib.

INTRODUCTION: The specific cutaneous toxicity of Bruton's tyrosine kinase inhibitors is poorly described. We report a case of severe systemic vasculitis induced by ibrutinib. OBSERVATION: A 73-year-old woman with chronic lymphocytic leukemia was treated with ibrutinib. Eighteen months after treatment onset, ulceronecrotic lesions on toes and tongue occurred. Skin biopsy found vasculitis of small and medium vessels. Biologic tests were negative. This vasculitis was refractory to systemic corticosteroid therapy and azathioprine. Ibrutinib was stopped on the hypothesis of drug-induced vasculitis. Skin lesions improved after discontinuation of ibrutinib. CONCLUSION: The mechanism of action of ibrutinib does not explain the occurrence of vasculitis and an immunoallergic mechanism is suspected.

Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

BACKGROUND: The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. METHODS: Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. RESULTS: The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. CONCLUSIONS: The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

BACKGROUND: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. PATIENTS AND METHODS: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101). RESULTS: In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy. CONCLUSION: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.

Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe de Moelle Osseuse et Thérapie Cellulaire and Eurocord.

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes.

This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1-1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.

Scleral lenses for severe chronic GvHD-related keratoconjunctivitis sicca: a retrospective study by the SFGM-TC.

Chronic GvHD-related keratoconjunctivitis sicca (cGvHD-related KCS) can significantly alter the quality of life of patients after allogeneic hematopoietic stem cell transplantation. The aim of this work was to assess the efficacy and tolerability of scleral lenses to treat severe cGvHD-related KCS. In this retrospective, multicenter study, we included 60 consecutive patients diagnosed with cGvHD-related KCS and fitted with scleral lenses. Patients were evaluated at baseline and at 2 months with the following tests: the Ocular Surface Disease Index (OSDI) to assess quality of life, the Oxford score to grade corneal damage and the logarithm of minimal angle of resolution (Log MAR) scale to determine visual acuity. We observed improvement in quality of life in 58 patients (97%). All parameters improved at 2 months. We observed significant differences at 2 months compared with baseline for the mean OSDI (86 versus 30, respectively, P<0.001), the mean Oxford score (3.2 versus 1.3, respectively, P<0.001) as well as visual acuity (Log MAR of 0.33 versus 0.10, respectively, P<0.001). Treatment with scleral lenses was discontinued in only 5 patients (8%) with a median follow-up of 20.5 months (range: 2-125 months). Scleral lenses were very efficient and well tolerated in patients with severe cGvHD-related KCS.

Carmustine replacement in intensive chemotherapy preceding reinjection of autologous HSCs in Hodgkin and non-Hodgkin lymphoma: a review.

High-dose chemotherapy preceding autologous hematopoietic stem cell transplantation (auto-HSCT) is one treatment option for patients with Hodgkin (HL) or non-Hodgkin lymphoma (NHL). The most frequently used intensive chemotherapy is a combination of carmustine (BCNU), etoposide, cytarabine and melphalan (BEAM). However, BCNU is consistently in short supply, and there has been a recent dramatic increase in its cost, necessitating the utilization of conditioning alternatives. The busulfan-based conditioning regimen known as the busulfan-cyclophosphamide-etoposide (BuCyE) combination is the second most-studied conditioning regimen worldwide after BEAM, and it exhibits a benefit/risk ratio that is comparable to that of BEAM. In addition to these two combinations, the present manuscript also summarizes data reported for other conditioning combinations. Owing to the lack of prospective and comparative studies, a comparison of the toxicities and medicoeconomical profiles of these treatments is warranted to identify effective replacements for BCNU-based conditioning.

Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan-cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged ⩾35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens.

Effect of immune modulation in relapsed peripheral T-cell lymphomas after post-allogeneic stem cell transplantation: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68-48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04-16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17-0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease.

In patients older than 55 years with AML in first CR, should we search for a matched unrelated donor when an old sibling donor is available?

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.

HLA-matched allogeneic stem cell transplantation improves outcome of higher risk myelodysplastic syndrome A prospective study on behalf of SFGM-TC and GFM.

Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only a curative treatment in patients with higher risk myelodysplastic syndrome (MDS), although demethylating agents (DMA) have been reported to improve survival. The advantage of HSCT over other treatment comes from retrospective studies and the aim of the current study was to prospectively test this hypothesis, analyzing in particular patients from the pre-transplant period to avoid the selection bias of performing transplantation. This study was conducted to compare overall survival in MDS patients candidates to transplantation according to donor availability. The majority of patients (76%) received a treatment with DMA after registration, 69% had a human leukocyte antigen (HLA)-identical donor, 70% of whom were transplanted. Baseline patient and disease characteristics were similar according to donor availability. Four-year overall survival was significantly better in patients with an HLA matched donor (37%) compared to patients without donor (15%). There was also evidence that this overall survival advantage was because of transplantation. Mortality risk was decreased after transplantation but it became significant only after the second year post transplant, because of early transplant-related mortality. Our results appear to justify, in higher risk MDS, a transplantation approach in all potential candidates who have an HLA identical donor.

90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas.

BACKGROUND: Patients with advanced B-cell non-Hodgkin's lymphoma (NHL) refractory to initial chemotherapy or relapsing after autologous stem-cell transplantation have a poor prognosis. Allogeneic stem-cell transplantation after reduced-intensity conditioning (RIC) regimen can be a therapeutic option. However, the high incidence of relapse remains a challenging issue. We speculated that the incorporation of (90)Y-Ibritumomab tiuxetan into a fludarabine-based RIC regimen would improve the lymphoma control without overwhelming toxicity. Our aim was to evaluate the safety of (90)Y-Ibritumomab tiuxetan in association with such a regimen in a prospective multicenter phase II trial. PATIENTS AND METHODS: Thirty-one patients with advanced lymphoma from five distinct institutions were included between February 2008 and October 2010. Thirty patients in complete or partial response after failure of a median of 3 (range, 2-4) previous chemotherapy regimens including autologous transplant in 29 were evaluable for nonrelapse mortality (NRM) at day 100 post-transplant that was the primary end point. RESULTS: With a median follow-up of 32 months (range, 29-60 months), the 2-year event-free and overall survivals of the whole study group were both 80% [95 confidence interval (CI) 60.8% to 90.5%). The 100-day and 2-year post-transplant cumulative incidences of NRM were 3.3% (95% CI 0.2% to 14.9%) and 13.3% (95% CI 5.4% to 33.2%), respectively. The 2-year cumulative incidence of relapse was 6.7% (95% CI 1.7% to 25.4%). The cumulative incidences of grade II-IV and extensive chronic graft-versus-host disease were 27% and 14%, respectively. CONCLUSIONS: For chemosensitive advanced high-risk B-cell lymphoma, the addition of (90)Y-Ibritumomab tiuxetan to a RIC regimen based on fludarabine, busulfan and antithymocyte globulin followed by allogeneic transplant is safe and highly effective. clinicaltrials.gov: NCT00607854.

Pre-transplantation risk factors to develop sclerotic chronic GvHD after allogeneic HSCT: a multicenter retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.

Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Française de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC).

Progression of Philadelphia-negative myeloproliferative (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) to acute myeloid leukemia (AML) is an adverse event in the course of the disease. Although allogeneic hematopoietic SCT (allo-SCT) is considered as the only curative therapy, few data exist on the outcome of patients with Philadelphia-negative MPN or MDS/MPN in blast phase who received an allo-SCT. Sixty patients were included in this retrospective study. AML was secondary to an MPN in 43 cases, whereas AML evolved from an MDS/MPN in 17 cases. Patients received allo-SCT in CR or advanced disease in 26 cases and 34 cases, respectively. With a median follow-up of 31 months (range, 25-44), OS and leukemia-free survival (LFS) were, respectively, 18% and 9% at 3 years. CR at transplant was associated with an improved LFS in univariate and multivariate analysis. The 3-year LFS was 18% for patients undergoing allo-SCT in CR versus 3% in advanced disease (P=0.008). Absence of thrombosis and an intermediate or favorable AML karyotype were associated with an improved outcome for patients who received allo-SCT in CR. New strategies are needed to improve the outcome of patients with MPN-MDS/MPN in blast phase.

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (P<0.001). In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (P<0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of <6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR=1.1), whereas there was a suggestion for higher relapse risk in patients given 6 mg/kg ATG (HR=1.4, P=0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC.

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation.

This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P<0.0.001) owing to high risk of nonrelapse mortality (NRM; HR=5.2, P<0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR=0.72; P=0.07) translating into a better OS (HR=1.8; P<0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR=0.65; P=0.02) but also with higher NRM (HR=3.5; P<0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (P<0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR=0.65; P=0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD.