Albert Esquirol

Umbilical cord blood transplantation in adults with advanced hodgkin's disease: high incidence of post‐transplant lymphoproliferative disease

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single‐unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74–98%] with a median of 18 d (range, 10–48). CI of acute graft‐versus‐host disease (GvHD) grades II–IV was 30% (95% C.I., 17–44%), while the incidence of chronic GVHD was 42% (95% C.I., 23–77%). The non‐relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13–46%) and 47% (95% C.I., 29–65%), respectively. EBV‐related post‐transplant lymphoproliferative disease (EBV‐PTLD) accounted for more than one‐third of transplant‐related death, with an estimate incidence of 26% (95% C.I., 9–44). The incidence of relapse at 4 yr was 25% (95% C.I., 9–42%). Four‐year event‐free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV‐PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.

Fludarabine/Busulfan versus Fludarabine/Melphalan Conditioning in Patients Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation for Lymphoma

There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Womens Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P = .002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P < .0001). The cumulative incidence of relapse at 1 year was 29% with FluBu and 10% with FluMel (P = .08). The 3-year disease-free survival rate was 47% with FluBu and 36% with FluMel (P = .24), and the 3-year overall survival rate was 62% with FluBu and 48% with FluMel (P = .01). In multivariable analysis, FluMel was associated with a higher risk of acute grades II to IV GVHD (HR, 7.45; 95% CI, 2.30 to 24.17; P = .001) and higher risk of NRM (HR, 4.87; 95% CI, 1.36 to 17.44; P = .015). The type of conditioning was not significantly associated with relapse or disease-free survival in multivariable models. However, conditioning regimen was the only factor significantly associated with overall survival: FluMel conditioning was associated with a hazard ratio for death of 2.78 (95% CI, 1.23 to 6.27; P = .014) compared with FluBu. In conclusion, the use of FluBu as conditioning for patients undergoing SCT for lymphoma was associated with a lower risk of acute GVHD and NRM and improved overall survival when compared with FluMel in our retrospective study. These results confirm the differences between these RIC regimens in terms of toxicity and efficacy and support the need for comparative prospective studies.

Impact of Cyclosporine Levels on the Development of Acute Graft versus Host Disease after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10–444), 219 (54–656), 253 (53–910) and 224 (30–699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2–4 aGVHD for a cumulative incidence of 45% (95% CI 34–50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P = 0.02) and development of grade 2–4 aGVHD (HR: 2.5, P < 0.01), while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease

This study aimed to characterize the incidence, etiology and outcome of infectious episodes in patients with steroid refractory acute GvHD (SR-GvHD). The cohort included 127 adults treated with inolimomab (77%) or etanercept (23%) owing to acute 2–4 SR-GvHD, with a response rate of 43% on day +30 and a 4-year survival of 15%. The 1-year cumulative incidences of bacterial, CMV and invasive fungal infection were 74%, 65% and 14%, respectively. A high rate (37%) of enterococcal infections was observed. Twenty patients (15.7%) developed BK virus-hemorrhagic cystitis and five percent had an EBV reactivation with only one case of PTLD. One-third of long-term survivors developed pneumonia by a community respiratory virus and/or encapsulated bacteria, mostly associated with chronic GvHD. Infections were an important cause of non-relapse mortality, with a 4-year incidence of 46%. In multivariate analysis, use of rituximab in the 6 months before SCT (hazard ratio; HR 4.2; 95% confidence interval; CI 1.1–16.3), severe infection before SR-GvHD onset (HR 5.8; 95% CI 1.3–26.3) and a baseline C-reactive protein >15 UI/mL (HR 2.9; 95% CI 1.1–8.5) were associated with infection-related mortality. High rates of opportunistic infections with remarkable mortality warrant further efforts to optimize long-term outcomes after SR-GvHD.

Transplant results in adults with Fanconi anaemia

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76–87%), acute graft‐versus‐host disease (GvHD) grade II–IV in 22% (95% CI 16–28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20–33). Non‐relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow‐up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non‐sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.

Impact of transplant eligibility and availability of a human leukocyte antigen-identical matched related donor on outcome of older patients with acute lymphoblastic leukemia

The role of allogeneic hematopoietic cell transplant (allo-HCT) in elderly patients with acute lymphoblastic leukemia (ALL) is unclear. We conducted a prospective study including 110 homogeneously treated patients with ALL aged 50–70 years. Their outcomes were analyzed by intention-to-treat on a donor-versus-no donor basis. Fifty-five patients (50%) underwent human leukocyte antigen (HLA) typing and were considered potential allo-HCT candidates, although only 25 (23%) eventually received an allo-HCT. Among potential allo-HCT candidates, patients with (n = 28) and without (n = 27) an HLA-identical sibling showed similar leukemia-free survival, overall survival (OS) and relapse risk, and the only variable associated with a better outcome was achievement of first complete remission (CR1) after induction therapy. Among the 25 patients who actually received an allo-HCT, the 4-year non-relapse mortality and OS were 42% (95% confidence interval 31–53%) and 37% (95% confidence interval 27–47%), respectively. In conclusion, having an HLA-identical sibling donor was not associated with a better outcome in patients with ALL aged 50–70 years.

Bone Marrow WT1 Levels in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplasia: Clinically Relevant Time Points and 100 Copies Threshold Value

The outcome of allogeneic hematopoietic stem cell transplantation (HCT) in patients with myeloid malignancies is better in those without minimal residual disease (MRD) than in those with MRD+, as assessed by multiparametric flow cytometry (MPFC). WT1 quantitation also has been used to assess the probability of relapse in acute myelogenous leukemia (AML) treated with chemotherapy. We analyzed the clinical value of normalized bone marrow WT1 levels as a measure of the expanded myeloid progenitor compartment in a consecutive series of 193 adult patients with myeloid malignancies who underwent HCT. Bone marrow WT1 levels before the HCT, at the first bone marrow aspirate after infusion, and in the follow-up samples after HCT were determined by means of real-time PCR using the European LeukemiaNet normalized method. We sought to clarify the prognostic relevance in terms of overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse (CIR). Based on earlier experience in AML, we selected a threshold of 100 copies, defining 2 groups: patients with <100 WT1 copies and those with ≥100 copies. Patients with <100 WT1 copies before HCT (median time, 36 days; range, 4 to 268 days) had a better OS, PFS, and CIR than those with ≥100 copies (40 ± 1 versus 29 ± 6 days, P = .004; 35 ± 9 versus 26 ± 6 days, P = .002; and 29 ± 7 versus 37 ± 6 days, P = .051). In the first bone marrow study after the HCT (median time, 42 days; range 14 to 157 days, respectively), patients with <100 WT1 copies also had better outcomes in terms of OS, PFS, and CIR (40 ± 7 versus 31 ± 9 days, P = .025; 36 ± 7 versus 30 ± 8 days, P = .004; and 29 ± 6 days versus 54 ± 9, P < .001, respectively). At this time point, bone marrrow samples with >100 copies also included patients who were negative for MRD as assessed by MPFC (19 of 32). During the HCT follow-up, patients with sustained WT1 levels <100 copies showed a marked benefit in terms of OS, PFS, and CIR even compared with those with only a single measurement >100 copies (mean, 68 ± 11 versus 26 ± 7 days, P < .001; 63 ± 11 versus 20 ± 8 days, P < .001; and 20 ± 8 vs. 71 ± 8 days, P < .001, respectively). Standardized bone marrow WT1 levels using a 100-copy threshold in samples obtained before HCT, at leukocyte recovery, and during follow-up provided relevant prognostic information in patients with myeloid malignacies submitted to HCT.

CD34+ Cell Selection versus Reduced-Intensity Conditioning and Unmodified Grafts for Allogeneic Hematopoietic Cell Transplantation in Patients Age >50 Years with Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34+ cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34+ cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS.

Pharmacogenetic analysis in the treatment of Hodgkin lymphoma

Abstract About 15–20% of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy ± radiotherapy still die following relapse or progressive disease. The outcome might be influenced by gene polymorphisms influencing chemotherapy metabolism. We studied 126 patients with HL treated with the ABVD regimen. We analyzed glutathione S-transferases (GSTT1, GSTM1 and GSTP1), cytochromes P450 (CYP3A4 and CYP2D6), UGT1A1 and BLMH gene polymorphisms and their association with clinical and outcome variables. Patients with a GSTM1 genotype associated with extensive or ultrahigh activity had a probability of 93.8% to achieve a complete response, while the remainder of the patients had a probability of 82.3% (p = 0.04). This variable maintained its statistical significance in multivariate analysis (hazard ratio 3.7, 95% confidence interval 1–13, p = 0.05). Patients with an extensive or ultrahigh GSTM1 genotype had better prognostic factors than those with poor or intermediate genotypes (hemoglobin level, p = 0.003; serum albumin, p = 0.05; and International Prognostic Score, p = 0.038). Thus, in the treatment of HL, clinical determinants might be more relevant than the pharmacogenetic parameters analyzed to date.

FcγRIIb expression in early stage chronic lymphocytic leukemia

Abstract In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d. Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients.