Jordi Sierra

Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft‐versus‐host disease after allogeneic transplantation

The graft‐versus‐host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo‐RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo‐RIC regimen groups, respectively (Pu2003<u20030·001), and was 39% vs. 29%, respectively (Pu2003=u20030·043), for grades 2–4 aGVHD. Only conditioning type (myeloablative versus allo‐RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR)u2003=u20032·16 [95% confidence interval (CI): 1·52–3·07], Pu2003<u20030·0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo‐RIC patients respectively (Pu2003=u20030·084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo‐RIC recipients [HRu2003=u20033·3 (95% CI: 1·42–8·08), Pu2003=u20030·0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo‐RIC group (7% vs. 25%, Pu2003=u20030·007). Duration of immunosuppression was shorter among allo‐RIC patients (35·5% vs. 68·8% required systemic immunosuppression 36u2003months after transplant, Pu2003=u20030·028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long‐term follow up when compared with myeloablative conditioning.

Chronic but not acute graft-versus-host disease improves outcome in multiple myeloma patients after non-myeloablative allogeneic transplantation.

Summary. The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan‐based non‐myeloablative allogeneic transplant (NMT) was evaluated. Event‐free survival (EFS) at 24u2003months was 33%, being significantly higher for patients who developed chronic graft‐versus‐host disease (cGVHD) when compared with those who did not [51%vs 0% respectively, Pu2003=u20030·02; hazard rateu2003=u20033·16 (95% confidence intervalu2003=u20031·09–9·15, Pu2003=u20030·03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43%vs 0% respectively, Pu2003=u20030·02). Overall survival (OS) at 24u2003months was 60%[72%vs 42% for patients who did and did not develop cGVHD respectively (Pu2003=u20030·1); 63%vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (Pu2003=u20030·013)]. At a median follow‐up of 366u2003d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant‐related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, Pu2003=u20030·04). The present study suggests that graft‐versus‐myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.

The effect of hormone replacement therapy on bone mass in patients with ovarian failure due to bone marrow transplantation

BACKGROUNDnLong permanent remissions in malignant hematopoietic disorders can often be achieved by autologous bone marrow transplantation (ABMT) or by allogenic bone marrow transplantation (BMT). Previous studies have shown that such therapies may induce osteoporosis due to iatrogenic ovarian failure. The administration of hormone replacement therapy (HRT) in these women could prevent the adverse effects of long-term ovarian failure without remarkable side effects. The aim of this study was to evaluate how the bone mass is affected by HRT in patients undergoing ABMT or BMT adjusting the results for age, weight, and height.nnnSUBJECTS AND METHODSnThirteen women with previous ABMT/BMT were treated with a standard dose (0.625 mg/day) of conjugated equine estrogen (CEE) or with 50 micrograms/day of 17-beta-estradiol in transdermal therapeutic systems (TTS) plus 5 mg/day of medroxyprogesterone acetate sequentially added to the last 12 days of estrogen therapy. Bone mass was measured prior to and 12 months following HRT. Blood samples were collected before therapy and during the 6th and 12th treatment months.nnnRESULTSnThe mean time elapsed between bone transplantation and HRT initiation was 13.0 months (range 3-26 months). Before treatment nine patients were osteopenic and after HRT bone mass increased in all cases. Following ABMT/BMT, hepatic hyperenzymemia was detected in three patients. After 6 and 12 months of treatment no significant changes were observed in hepatic enzymes.nnnCONCLUSIONnAlthough hepatic hyperenzymemia is commonly considered as a contraindication for HRT, our results suggest that HRT is safe for these patients and that such therapy should be initiated after transplantation in women to prevent adverse effects of long-term ovarian failure.

Cardiac chimerism in recipients of peripheral-blood and bone marrow stem cells.

Multipotent progenitor cells have the ability to differentiate into most somatic cell types, including cardiac myocytes. We sought to investigate cardiac chimerism after peripheral‐blood and bone marrow stem cell transplantation. Between 10 and 17 highly polymorphic short tandem repeat (STR) markers were assayed in DNA obtained from donors’ peripheral blood, recipients’ peripheral blood before transplantation, and the recipients heart in every patient. Gender and non‐gender STR donor alleles were identified in the recipient heart in three patients. Using a highly sensitive PCR assay to determine donor and recipient genotypes, we confirmed the existence of cardiac chimerism in recipients of peripheral‐blood and bone marrow stem cells.

Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors that have been implicated in tumoral transformation, especially in hematological malignancies. Because of this, the JAK/STAT pathway is attractive as a therapeutic target in these tumors. In the present study, we analyzed the ability of fludarabine and two JAK kinase inhibitors, AG490 and WHI-P131, to block STAT1 activation and induce apoptosis on B-cell chronic lymphocytic leukemia (B-CLL) cells. All drugs were able to induce a high percentage of apoptosis on B-CLL cells from all patients studied. However, only AG490 and WHI-P131 were able to strongly suppress the STAT1 activation of B-CLL cells. In conclusion, our data show that JAK kinase inhibitors, such as AG490 and WHI-P131 are able to inhibit the STAT1 pathway on B-CLL cells and are strong inductors of apoptosis on these cells.

Unrelated transplantation for poor-prognosis adult acute lymphoblastic leukemia: long-term outcome analysis and study of the impact of hematopoietic graft source.

Adults with high-risk acute lymphoblastic leukemia (HR-ALL) have a poor outcome with standard chemotherapy and usually undergo unrelated stem cell transplantation (SCT) if a matched sibling donor is not available. We analyzed the outcome of adult patients with unrelated SCT for HR-ALL and studied the possible effect of the hematopoietic stem cell source of the transplant. A total of 149 adult patients (median age, 29 years, range, 15-59 years) with HR-ALL underwent unrelated SCT in 13 Spanish institutions between 2000 and 2007. Patients in first complete remission (CR1) at transplantation had at least one adverse prognostic factor (advanced age, adverse cytogenetics, hyperleukocytosis, or slow response to induction therapy). ALL was in CR1 in 81 patients (54%), in second CR (CR2) in 37 patients (25%), in third CR (CR3) in 11 patients (7%), and with overt disease in 20 patients (13%). The hematopoietic source was unrelated cord blood (UCB) in 62 patients and an unrelated donor (UD) in 87 patients. The patients undergoing UCB-SCT and UD-SCT were comparable in terms of the main clinical and biological features of ALL, except for a higher frequency of patients with more overt disease in the UCB-SCT group. There was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) at 5 years between the 2 groups. Treatment-related mortality (TRM) was significantly lower in the UCB-SCT group (P = .021). The probability of relapse at 1 year was 17% (95% confidence interval [CI], 7%-27%) for the UD-SCT group and 27% (95% CI, 14%-40%) for the UCB-SCT group (P = .088), respectively. Only disease status at transplantation (CR1, 41% [95% CI, 18%-64%] vs CR2, 51% [95% CI, 17%-85%] vs advanced disease, 66% [95% CI, 46%-86%]; P = .001) and the absence of chronic graft-versus-host disease (74% [95% CI, 46%-100%] vs 33% [95% CI, 17%-49%]; P = .034) were significant factors for relapse. All unrelated transplantation modalities were associated with high treatment-related mortality for adult HR-ALL patients without a sibling donor. UCB-SCT and UD-SCT were found to be equivalent options. Disease status at transplantation and chronic GVHD were the main factors influencing relapse in both transplantation modalities.

The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate

Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus, due to a lower risk of chronic graft-versus-host disease and non-relapse mortality, which translates into better event-free and overall survival rates, in comparison with those achieved with cyclosporine + mycophenolate. This trial was registered at www.clinicaltrials.gov as 2007-006416-32 by GEL-TAMO/GETH.

Reduced-Intensity Conditioning Allogeneic Transplantation from Unrelated Donors: Evaluation of Mycophenolate Mofetil Plus Cyclosporin A as Graft-versus-Host Disease Prophylaxis

In the current study, we have analyzed the efficacy of cyclosporine A (CSA) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in the fludarabine plus melphalan or busulfan reduced intensity regimen (RIC) setting in a series of 44 patients receiving allogeneic transplantation from an unrelated donor. Only 23% were in the first complete remission at the time of transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD (aGVHD) was 53% and 23%, respectively. Fifty-six percent had equal to or greater than grade 2 gut involvement. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 93% and 63%, respectively. Ninety-two percent of patients who were evaluable +100 days after transplant were in complete remission. Relapse rate was 25% at 2 years. Event free (EFS) and overall survival (OS) at 2 years were 52%. Pharmacokinetic assays of mycophenolic acid (MPA) showed a therapeutic area under the curve (AUC) at the dosage of 3 g daily, although a large inter- and intraindividual variations of MPA plasma levels were found. In conclusion, the combination of CSA plus MMF in the fludarabine plus melphalan or busulfan RIC setting is feasible. Regarding GVHD, this combination allowed to control aGVHD but lead to a high incidence of cGVHD, so that newer strategies are required, especially in trying to decrease gastrointestinal involvement.

Positive selection for CD34+ reduces the incidence and severity of veno-occlusive disease of the liver after HLA-identical sibling allogeneic peripheral blood stem cell transplantation

OBJECTIVEnT-cell depletion (TCD), primarily developed to prevent graft-vs-host disease (GVHD), might reduce early liver dysfunction after allogeneic hematopoietic stem cell transplantation. However, no comparative studies have been performed to investigate this. We analyzed the influence of selection for CD34(+) cells on the incidence and severity of hepatic veno-occlusive disease (VOD).nnnPATIENTS AND METHODSnFive hundred and one patients who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from HLA-identical siblings were included in the present study. Two hundred and ninety patients (59%) were grafted with CD34+ positively selected grafts and 211 (41%) with nonmanipulated grafts. Their mean age was 38 years (range 17-63). All patients had hematological malignancies and 96% were conditioned with combinations either of cyclophosphamide plus total-body irradiation or of cyclophosphamide plus busulphan. Most of the patients received GVHD prophylaxis with methotrexate (MTX) or cyclosporin A.nnnRESULTSnFifty-two patients (10.4%) developed VOD. VOD was more frequent in patients receiving nonmanipulated grafts (16.1% vs 6.2%; p<0.0009), in those with a Karnofsky score less than 90 (17.5% vs 7.8%; p=0.001), and with the use of MTX for GVHD prophylaxis (14.8% vs 7%; p=0.005). In multivariate analyses, only CD34+ positive selection (p=0.0007) and Karnofsky score (p=0.004) emerged as independent risk factors for VOD. The same effect was observed in the subset of patients with severe VOD.nnnCONCLUSIONnThese findings show that CD34+ selection not only decreases the incidence of GVHD but also prevents VOD after HLA-identical sibling PBSCT.

Bacteremia by Gram-Negative Bacilli in Patients with Hematologic Malignancies

To compare the characteristics of bacteremic infections by different aerobic gram-negative bacilli (GNB) in patients with hematologic malignancies, we studied 54 consecutive monomicrobial bacteremias by Enterobacteriaceae (EB), 15 by Pseudomonas aeruginosa, 43 by other non-glucose-fermenting GNB (NGFGNB) and 11 by other GNB. Patients with EB and P. aeruginosa bacteremia usually developed the infection after intensive chemotherapy for leukemia or during a hematopoietic stem cell transplantation, while most infections in outpatients off therapy were due to NGFGNB. A significant proportion of bacteremias by EB (37%) and P. aeruginosa (40%) were accompanied by severe morbidity (septic shock, pneumonia or deep-seated organ infections) vs. only 7% of other NGFGNB (p < 0.01). Most infections by these latter bacteria were catheter-related bacteremias (80 vs. 2% of EB, p < 0.005), while most EB infections (61%) were uncomplicated bacteremias of unknown source (vs. 14% of other NGFGNB, p < 0.005). Appropriate antibiotics alone cured 98% of EB and 73% of P. aeruginosa bacteremias but only 26% of other NGFGNB (p < 0.005 for both differences), which were cured by catheter removal in 70%, usually after failure of antibiotic treatment. In conclusion, our results suggest that there are significant differences in the patient populations and clinical characteristics of bacteremic infections by the classic GNB (EB and P. aeruginosa) and the new NGFGNB in adults with hematologic malignancies.