Pere Barba

Treatment of High-Risk Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia in Adolescents and Adults According to Early Cytologic Response and Minimal Residual Disease After Consolidation Assessed by Flow Cytometry: Final Results of the PETHEMA ALL-AR-03 Trial

PURPOSE Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation. PATIENTS AND METHODS Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 × 10(-4) at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level ≥ 5 × 10(-4). RESULTS Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (≥ 1 × 10(-3) after induction and ≥ 5 × 10(-4) after early consolidation) as the only prognostic factor for DFS and OS. CONCLUSION Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.

Comparison of Two Pretransplant Predictive Models and a Flexible HCT-CI Using Different Cut off Points to Determine Low-, Intermediate-, and High-Risk Groups: The Flexible HCT-CI Is the Best Predictor of NRM and OS in a Population of Patients Undergoing allo-RIC

Patient comorbidities are being increasingly analyzed as predictors for outcome after hematopoietic stem cell transplantation (HSCT), especially in allogeneic HSCT (Allo-HSCT). Researchers from Seattle have recently developed several pretransplant scoring systems (hematopoietic cell transplantation comorbidity index [HCT-CI] and the Pretransplantation Assessment of Mortality (PAM) model) from large sets of HSCT recipients with the aim of improving non-transplant models, mainly the Charlson Comorbidity Index (CCI). The validation of these comorbidity indexes in other institutions and in different disease and conditioning-related settings is of interest to determine whether these models are potentially applicable in clinical practice and in research settings. We performed a retrospective study in our institution including 194 consecutive reduced-intensity conditioning (RIC) AlloHSCT (allo-RIC) recipients to compare the predictive value of the PAM score, CCI, the original HCT-CI, and the flexible HCT-CI using a different risk group stratification. The median patient pretransplant scores for the HCT-CI, PAM, and CCI were 3.5, 22, and 0, respectively. The flexible HCT-CI risk-scoring system (restratified as: low risk [LR] 0-3 points, intermediate risk [IR] 4-5 points, and high risk [HR] >5 points) was the best predictor for non-relapse mortality (NRM). The 100-day and 2-year NRM incidence in these risk categories was 4% (95% confidence interval C.I. 2%-11%), 16% (95% C.I. 9%-31%), and 29% (95% C.I. 19%-45%), respectively (P < .001), and 19% (95% C.I. 12%-28%), 33% (95% C.I. 22%-49%), and 40% (95% C.I. 28%-56%), respectively (P=.01). However, we found no predictive value for NRM using neither the original HCT-CI nor the PAM or CCI models. The better predictive capacity for NRM of the flexible HCT-CI than PAM and CCI was confirmed with the c-statistics (c-statistics of 0.672, 0.634, and 0.595, respectively). Regarding the 2-year overall survival (OS), the flexible HCT-CI score categories were also associated with the highest predictive HR. In conclusion, our single-center study suggests that the flexible HCT-CI is a good predictor of 2-year NRM and survival after an allo-RIC.

Early and Late Neurological Complications after Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation

Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140 mg/m(2) (n=119), cyclophosphamide (Cy) 120 mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval [CI] 11-23). CNS complications included nonfocal encephalopathies in 11 patients, meningoencephalitis in 5 patients, and stroke or hemorrhage in 4. PNS complications consisted of 5 cases of mononeuropathies and 3 cases of polyneuropathies. Drug-related toxicity was responsible for 10 of the 31 events (32%) (8 caused by CsA). Interestingly, 14 of the 23 CNS events (61%) and only 1 of the 8 PNS complications (13%) appeared before day +100 (P=.01). Overall, patients presenting NC showed a trend for higher 1-year nonrelapse mortality (NRM) (37% versus 20%, P=.08). In patients with CNS involvement, 1-year NRM was significantly worse (42% versus 20%, P=.02). CNS NC also had a negative impact on 4-year overall survival (OS; 33% versus 45%, P=.05). In conclusion, our study showed that NC are observed after allo-RIC and have diverse features. NC affecting the CNS have earlier onset and worse outcome than those involving the PNS.

Invasive Aspergillosis Complicating Pandemic Influenza A (H1N1) Infection in Severely Immunocompromised Patients

We report 5 cases of invasive aspergillosis occurring in severely immunosuppressed patients hospitalized with pandemic influenza A (H1N1). We suggest that infection with influenza A (H1N1) may predispose immunocompromised patients to develop invasive aspergillosis. Physicians should be aware of this potential association to allow early diagnosis and prompt treatment of aspergillosis.

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.

Dose-intensive chemotherapy including rituximab in Burkitt's leukemia or lymphoma regardless of human immunodeficiency virus infection status: final results of a phase 2 study (Burkimab).

The use of rituximab together with intensive chemotherapy in Burkitts lymphoma or leukemia (BL) has been scarcely explored. This study prospectively evaluated and compared the outcome and toxicity of human immunodeficiency virus (HIV)‐positive and HIV‐negative patients with BL who were treated in an intensive immunochemotherapy‐based and age‐adapted trial.

Study of Kidney Function Impairment after Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation. A Single-Center Experience

Acute renal failure (ARF) is a life-threatening complication after allogeneic stem cell transplantation (Allo-HSCT). Identification of ARF risk factors could be useful to develop preventive strategies for patients at high risk. The goal of this study was to evaluate the incidence and risk factors of ARF after reduced intensity conditioning Allo-HSCT (Allo-RIC). We included 188 consecutive patients who underwent Allo-RIC in our center between January 1999 and December 2006. ARF was defined as a decrease of at least 25% in baseline estimated glomerular filtration rate (GFR) calculated by modification of diet in renal disease (MDRD) equation. Conditioning consisted of fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10 mg/kg (n = 61), melphalan (Mel) 140 mg/m(2) (n = 115), cyclophosphamide (Cy) 120 mg/kg (n = 7) or low-dose total-body irradiation (TBI) 2 Gy (n = 5). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) alone (n = 3) or in addition to methotrexate (MTX; n = 132) or mycophenolate mofetil (MMF; n = 51). The cumulative incidence of ARF at 1 year was 52% (n = 97 patients) after Allo-RIC. Most cases (86%) occurred within the first 3 months, and the main cause was the administration of CsA (71%). The risk factors associated with ARF in multivariate analysis were: administration of MTX (hazard ratio [HR] 1.9, P =.02), more than 3 lines of therapy prior to Allo-RIC (HR 1.8, P = .01), diabetes mellitus (HR 2.1, P < .01), and GVHD grade III-IV (HR 2.1, P = .015). In multivariate analysis, ARF was an independent risk factor for 1-year nonrelapse mortality (NRM) (HR 3, 95% confidence interval [CI]: 1.5-6, P = .002). Patients who experienced ARF had lower 1-year overall survival (OS; 53% versus 74%, P < .05). ARF is a frequent complication in patients after Allo-RIC, and it has a negative impact on outcome. Identification of ARF risk factors could help to avoid exposure to nephrotoxic drugs during the follow-up in patients at high risk.

The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis

Myelofibrotic transformation is a well-recognized complication of essential thrombocythemia (ET) and polycythemia vera (PV).[1][1],[2][2] However, information is scarce on the life expectancy and prognostic factors of patients developing this complication.[1][1],[3][3]–[5][4] Prognostic models

Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

Combination of the Hematopoietic Cell Transplantation Comorbidity Index and the European Group for Blood and Marrow Transplantation Score Allows a Better Stratification of High-Risk Patients Undergoing Reduced-Toxicity Allogeneic Hematopoietic Cell Transplantation

This study was conducted to determine whether the integration of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT) score would improve individual capacity for stratification of high-risk HCT candidates. A total of 442 consecutive patients receiving an allogeneic HCT after reduced-toxicity conditioning was included. Final HCT-CI and EBMT scores were calculated and validated. Then, patients were grouped into a 6-category new combination model according to the HCT-CI (0, 1 to 2, ≥ 3) and EBMT scores (0 to 3, 4 to 7), and the models predictive capacity was also evaluated. Median HCT-CI and EBMT scores were 3 and 4, respectively. Increased HCT-CI was associated with higher 4-year nonrelapse mortality (NRM) and lower 4-year overall survival (OS), whereas a high EBMT score was associated with higher 4-year NRM. The HCT-CI showed a trend for a better predictive capacity than the EBMT score (c-statistic .6 versus .54, P = .1). According to the new model, patients within HCT-CI of 0 and HCT-CI of 1 to 2 groups had similar risk of NRM independently of their EBMT score. Within the HCT-CI ≥ 3 group, patients with low EBMT score showed lower NRM (25% versus 40%, P = .04) and a trend to higher OS (52% versus 36%, P = .06) than patients with a high EBMT score. Moreover, patients with HCT-CI ≥ 3 and EBMT score 0 to 3 had similar outcomes than those with HCT-CI of 1 to 2. In conclusion, the combination of HCT-CI and the EBMT score is feasible and might contribute to a better identification of high-risk patients, improving selection of best allogeneic HCT candidates.