Impact of pre- and/or post-autologous stem cell transplantation exposure to brentuximab vedotin on survival outcomes in patients with high-risk Hodgkin lymphoma.

The AETHERA trial demonstrated that brentuximab vedotin (BV) consolidation after autologous stem cell transplantation (ASCT) in patients with Hodgkin lymphoma (HL) at high risk of relapse/progression increases progression-free survival (PFS). Patients previously exposed to BV were excluded from that trial. However, BV alone or in combination with chemotherapy is frequently used as front-line treatment and/or pre-ASCT salvage therapy. We analyzed data from 156 patients with high-risk HL who underwent ASCT with (BV-CON, n = 62) or without (non-BV, n = 94) BV consolidation. Fifty-seven patients received BV-based salvage regimens before ASCT. The 3-year overall survival and PFS for all patients were 91.6% and 70.0%, respectively. Multivariate analysis showed that BV-CON was associated with better PFS (HR 0.39, p = 0.01), whereas positive PET at transplant leaded to worse PFS (HR 2.71, p = 0.001). BV-CON improved PFS in PET-positive patients (72.2% vs. 43.0%, p = 0.05), with a beneficial trend observed in PET negative (88.8% vs. 75.2%, p = 0.09). BV-CON patients with or without BV exposure pre-ASCT had a significantly better PFS than non-BV with or without BV pretransplant treatment (HR 0.36, p = 0.004). The efficacy of real-life BV consolidation therapy was similar to that in the AETHERA trial. This therapeutic strategy improves survival independently of BV exposure prior to ASCT.

Balanced and unbalanced translocations in a multicentric series of 2843 patients with chronic lymphocytic leukemia.

Chromosomal translocations in chronic lymphocytic leukemia (CLL) are very rare, and therefore systematic analysis of large series of cases is needed to allow the identification of recurrent rearrangements, breakpoints involved, and target genes. The aims of the present study were to identify new translocations and their clinical impact and to establish their frequency in a large cohort of 2843 CLL patients. By conventional cytogenetics 250 translocations were identified in 215 (7.5%) patients, 186 (74%) were apparently balanced and 64 (26%) were unbalanced. All chromosomes were involved in translocations, except Y chromosome. The chromosomes more frequently translocated were in decreasing frequency chromosomes 14, 18, 13, 17, 1, 6, 2, 3, 8, and 11. Translocations were found in the karyotypes either as the unique chromosomal abnormality (27%), associated with another alteration (24%), or as a part of a complex karyotype (CK, 48%). A large proportion of rearranged breakpoints involved genes related to CLL such as IGH (14q32), RB1, MIR15A, MIR16-1 (13q14), BCL2 (18q21), IGL (22q11.2), TP53 (17p13), IRF4 (6p25-p23), ATM (11q22), and CDK6 (7q21). Overall, 76 novel CLL translocations were identified, including a recurrent t(8;11)(p21;q21-23). Whole-genome sequencing and/or copy-number microarray data of 24 cases with translocations confirmed all rearrangements, enabled refinement of 3 karyotypes and all breakpoints at gene level. The projected survival and time to first treatment significantly decreased linearly with the number of translocations. In summary, this study allowed to establish the frequency of translocations (7.5%) and to identify new translocations in a cohort of 2843 CLL patients.

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.

BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.

Real-world data on survival improvement in patients with multiple myeloma treated at a single institution over a 45-year period.

The prognostic landscape of multiple myeloma (MM) has evolved significantly over the last few decades. There are, however, few data measuring such improvement in real-world patients. This study aimed to investigate trends in survival improvement over 45 years, and the associated clinical factors, in an unselected population of patients with MM. Between 1970 and 2015, 1 161 MM patients were included. Patients were classified into three calendar periods (1970-1984, 1985-1999, and 2000-2015), according to the treatment received; polychemotherapy, autologous stem cell transplantation, and novel drugs respectively. We analysed relative survival (RS) to accurately evaluate MM-related death rates after excluding the mortality expected in the general population. RS at five years increased from 27% in 1970-1984 to 38% and 56% in the next two calendar periods respectively. The improvement to survival was greater in the younger population, but it was also observed in elderly patients and those with poor performance status and more advanced disease. Although myeloma is still a non-curable disease, encouraging results have been observed in the last decades. Progress is expected to continue with the use of new generations of anti-myeloma drugs, and will, hopefully, be documented in real-world patients by the appropriate population-based studies.

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis.

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

Efficacy of early transfusion of convalescent plasma with high-titer SARS-CoV-2 neutralizing antibodies in hospitalized patients with COVID-19.

BACKGROUND: Despite most controlled trials have shown no measurable benefit of COVID-19 convalescent plasma (CCP) in patients with COVID-19, some studies suggest that early administration of CCP with high-titer anti-SARS-CoV-2 can be beneficial in selected patients. We investigated the efficacy of early administration of high-titer CCP to patients with COVID-19 who required hospitalization, STUDY DESIGN AND METHODS: Observational, propensity score (PS) matched case-control study of COVID-19 patients treated with CCP within 72 h of hospital admission and untreated controls from August 2020 to February 2021. All CCP donations had a Euroimmun anti-SARS-CoV-2 sample-to-cutoff ratio ≥3. PS matching was based on prognostic factors and presented features with high-standardized differences between the treated and control groups. The primary endpoint was mortality within 30 days of diagnosis. RESULTS: A total of 1604 patients were analyzed, 261 of whom received CCP, most (82%) within 24 h after admission. Median age was 67 years (interquartile range: 56-79), and 953 (60%) were men. Presenting factors independently associated with higher 30-day mortality were increased age, cardiac disease, hypoxemic respiratory failure, renal failure, and plasma d-dimer >700 ng/ml. After PS matching, transfusion of CCP was associated with a significant reduction in the 30-day mortality rate (odds ratio [OR]; 0.94, 95% confidence interval [CI]: 0.91-0.98; p = .001) that extended to the 60th day after COVID-19 diagnosis (OR: 0.95; 95% CI: 0.92-0.99; p = .01). CONCLUSION: Our results suggest that CCP can still be helpful in selected patients with COVID-19 and call for further studies before withdrawing CCP from the COVID-19 therapeutic armamentarium.

Mortality in acquired thrombotic thrombocytopenic purpura in the pre-caplacizumab era.

Despite the effectiveness of plasma exchange (PEX) and immunosuppressants in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP), a number of patients still die as a result of the disease. Whether caplacizumab could rescue these patients remains still unsettled. The objective of this study was to characterise mortality patterns and prognostic factors in the first episode of aTTP.We queried the Spanish TTP Registry for patients with a diagnosis of aTTP in their presenting episode who fulfilled complete clinical and follow-up data (n = 102). The patients were diagnosed between 2004 and 2018, and all were treated with daily PEX and corticosteroids. Clinical and laboratory data were analysed at diagnosis and during the treatment course.Eight patients (7.7%) died between 12 h and 36 days after presentation, and could be classified into three patterns: death before treatment, early death driven by acute cardiac or neurologic events, and late death due to unremitted aTTP. Stupor or coma at diagnosis and platelet count < 20 × 109 /L by the 6th treatment day were independently associated with increased risk of death.Stupor or coma at diagnosis and lack of response to PEX by the 6th day in patients experiencing the first episode of aTTP are strong predictors of mortality. These patients could be rescued by novel agents aimed at halting the microvascular thrombosis until adequate immunosuppression is achieved.

Vasovagal syncope after blood donation in active duty military personnel of the Spanish Army.

BACKGROUND: All studies of vasovagal syncope (VVS) after blood donation have been performed with civilian donors. We hypothesized that military donors have a lower incidence of VVS and a particular set of predisposing factors. STUDY DESIGN AND METHODS: Retrospective case-control study matching every case of VVS seen from 2011 to 2019 with two controls without VVS from the same blood drive. We used the odds ratio (OR) and its 95% confidence interval (CI), estimated by multivariate logistic regression, to identify independent predictors of VVS. RESULTS: There were 105 episodes of VVS among 65.481 whole blood donations (0.15%). VVS was more frequent among donors from military academies than from other military units (0.37% vs. 0.10%, p < .001) and in collections conducted in mobile inside setups than in mobile buses (0.23% vs. 0.06%, p < .001). In the multivariate analysis, the only independent predictors of VVS were the status of first-time donor (OR 2.6, 95% CI 1.5-4.4; p < .001) and pre-donation systolic blood pressure (SBP) < 120 mm Hg (OR 1.9, 95% CI 1.1-3.3; p = .01). Donors with both risk factors had a 5.5-fold increased risk of VVS than donors without any risk factor. Age and female sex were not predictive of VVS. DISCUSSION: Active duty military blood donors have a lower incidence of VVS than that reported in civilian donors. First-time donors and donors with SBP < 120 mm Hg should be temporarily deferred when immediate reincorporation to hazardous or strenuous duty tasks after donation is inescapable.

Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of EBMT and the Spanish Myelofibrosis Registry.

Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly used in older myelofibrosis (MF) patients, but its risk/benefit ratio compared to non-transplant approaches has not been evaluated in this population. We analyzed the outcomes of allo-HCT in 556 MF patients aged ≥65 years from the EBMT registry, and determined the excess mortality over the matched general population of MF patients ≥65 years managed with allo-HCT (n = 556) or conventional drug treatment (n = 176). The non-transplant cohort included patients with intermediate-2 or high risk DIPSS from the Spanish Myelofibrosis Registry. After a median follow-up of 3.4 years, the estimated 5-year survival rate, non-relapse mortality (NRM), and relapse incidence after transplantation was 40%, 37%, and 25%, respectively. Busulfan-based conditioning was associated with decreased mortality (HR: 0.7, 95% CI: 0.5-0.9) whereas the recipient CMV+/donor CMV- combination (HR: 1.7, 95% CI: 1.2-2.4) and the JAK2 mutated genotype (HR: 1.9, 95% CI: 1.1-3.5) predicted higher mortality. Busulfan-based conditioning correlated with improved survival due to less NRM, despite its higher relapse rate when compared with melphalan-based regimens. Excess mortality was higher in transplanted patients than in the non-HCT cohort in the first year of follow-up (ratio: 1.93, 95% CI: 1.13-2.80), whereas the opposite occurred between the fourth and eighth follow-up years (ratio: 0.31, 95% CI: 0.18-0.53). Comparing the excess mortality of the two treatments, male patients seemed to benefit more than females from allo-HCT, mainly due to their worse prognosis with non-transplant approaches. These findings could potentially enhance counseling and treatment decision-making in elderly transplant-eligible MF patients.

Predicting Survival after Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis: Performance of the Myelofibrosis Transplant Scoring System (MTSS) and Development of a New Prognostic Model.

Accurate prognostic tools are crucial to assess the risk/benefit ratio of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with myelofibrosis (MF). We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System (MTSS) and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo-HCT. After a median follow-up of 3.1 years, 47% of patients had died, and the estimated 5-year survival rate was 51%. Projected 5-year risk of nonrelapse mortality and relapse incidence was 30% and 20%, respectively. Factors independently associated with increased mortality were a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥3 and receiving a graft from an HLA-mismatched unrelated donor or cord blood, whereas post-transplant cyclophosphamide (PT-Cy) was associated with improved survival. Donor type was the only parameter included in the MTSS model with independent prognostic value for survival. According to the MTSS, 3-year survival was 62%, 66%, 37%, and 17% for low-, intermediate-, high-, and very high-risk groups, respectively. By pooling together the low- and intermediate-risk groups, as well as the high- and very high-risk groups, we pinpointed 2 categories: standard risk and high risk (25% of the series). Three-year survival was 62% in standard-risk and 25% in high-risk categories (P < .001). We derived a risk score based on the 3 independent risk factors for survival in our series (donor type, HCT-CI, and PT-Cy). The corresponding 5-year survival for the low-, intermediate-, and high-risk categories was 79%, 55%, and 32%, respectively (P < .001). In conclusion, the MTSS model failed to clearly delineate 4 prognostic groups in our series but may still be useful to identify a subset of patients with poor outcome. We provide a simple prognostic scoring system for risk/benefit considerations before transplantation in patients with MF.

IgA Nephropathy Recurrence after Kidney Transplantation: Role of Recipient Age and Human Leukocyte Antigen-B Mismatch.

BACKGROUND: Recurrence of immunoglobulin (Ig)A nephropathy (rIgAN) is a growing cause of kidney allograft dysfunction. This study was aimed at investigating factors associated with rIgAN and the subsequent progression to end-stage renal disease (ESRD). METHODS: Retrospective study including consecutive patients with IgA nephropathy (IgAN) who received a kidney transplant in our center between 1992 and 2016 and had a renal biopsy by clinical indication. The date of detection of chronic kidney disease (CKD) 5 was used as renal outcome. RESULTS: Eighty-six kidney transplants were performed in patients with IgAN, 38 (44%) were from living donors (related n = 26). rIgAN was diagnosed in 23 allografts (27%). Renal function and proteinuria at the end of the follow-up period were worst in the rIgAN patients compared to those without rIgAN (2.2 vs. 1.4 mg/dL, p = 0.014, and 1.16 vs. 0.49 g/day, p = 0.005, respectively). Risk of rIgAN and progression to CKD 5 decreased with patient's age (hazard ratio [HR] 0.95, 95% CI 0.92-0.98, p = 0.002, and HR 0.97, 95% CI 0.83-0.97, p = 0.008 per year, respectively). Patients with rIgAN had a higher risk of progression to CKD 5 (HR 6.7, 95% CI 1.3-35.7, p = 0.025). Full donor-recipient mismatch in the human leukocyte antigen (HLA)-B loci decreased the risk of rIgAN (HR 0.22, 95% CI 0.06-0.76, p = 0.017). CONCLUSIONS: rIgAN was an independent risk factor for ESRD after renal allograft. Younger age increased the risk of rIgAN and CKD 5. Conversely, HLA-B mismatching was a potential protective factor for rIgAN of this glomerular disease.

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

Positive direct antiglobulin test in post-artesunate delayed haemolysis: more than a coincidence?

BACKGROUND: Delayed haemolysis is a frequent adverse event after treatment with artesunate (AS). Removing once-infected "pitted" erythrocytes by the spleen is the most accepted mechanism of haemolysis in these cases. However, an increasing number of cases with positive direct antiglobulin test (DAT) haemolysis after AS have been reported. METHODS: All malaria cases seen at Hospital Clinic of Barcelona between 2015 and 2017 were retrospectively reviewed. Clinical, parasitological and laboratory data from patients treated with intravenous artesunate-specifically looking for delayed haemolysis and DAT-was collected. RESULTS: Among the 36 severe malaria patients treated with artesunate at the hospital, 10 (27.8%) developed post-artesunate delayed haemolysis. Out of these, DAT was performed in six, being positive in four of them (at least 40%). DAT was positive only for complement-without IgG-suggesting drug-dependent immune-haemolytic anaemia of the immune-complex type. Three of the four patients were treated with corticosteroids and two also received blood transfusion, with a complete recovery. CONCLUSIONS: Drug-induced auto-immune phenomena in post-artesunate delayed haemolysis may be underreported and must be considered. The role of corticosteroids should be reassessed.

Single Antigen-Mismatched Unrelated Hematopoietic Stem Cell Transplantation Using High-Dose Post-Transplantation Cyclophosphamide Is a Suitable Alternative for Patients Lacking HLA-Matched Donors.

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is not defined. The use of high-dose post-transplant cyclophosphamide (PTCy) in haploidentical transplantation has proven feasible and effective in overcoming the negative impact of HLA disparity on survival. We hypothesized that PTCy could also be effective in the setting of MMUD transplantation. We retrospectively analyzed 86 consecutive adult recipients of alloHSCT in our institution, comparing 2 contemporaneous groups: PTCy MMUD (n = 26) versus matched unrelated donor (MUD) (n = 60). Graft source was primarily peripheral blood (92%). All PTCy MMUD were HLA 7/8 (differences in HLA class I loci in 92% of patients) and received PTCy plus tacrolimus ± mofetil mycophenolate as GVHD prophylaxis. No differences were observed between PTCy MMUD and MUD in the 100-day cumulative incidence of acute GVHD grades II to IV (31% versus 22%, respectively; P = .59) and III to IV (8% versus 10%, P = .67). There was a trend for a lower incidence of moderate to severe chronic GVHD at 1 year after PTCy MMUD in comparison with MUD (22% versus 41%, P = .098). No differences between PTCy MMUD and MUD were found regarding nonrelapse mortality (25% versus 18%, P = .52) or relapse rate (11% versus 19%, P = .18). Progression-free survival and overall survival at 2 years were similar in both cohorts (67% versus 54% [HR, .84; 95% CI, .38 to 1.88; P = .68] and 72% versus 57% [HR, .71; 95% CI, .31 to 1.67; P = .44], respectively). The 2-year cumulative incidence of survival free of moderate to severe chronic GVHD and relapse tended to be higher in the PTCy MMUD group (47% versus 24%; HR, .60; 95% CI, .31 to 1.14; P = .12). We conclude that HLA 7/8 MMUD transplantation using PTCy plus tacrolimus is a suitable alternative for those patients who lack a MUD.

Prognostic risk models for transplant decision-making in myelofibrosis.

Prognostic models are widely used in clinical practice for transplant decision-making in myelofibrosis (MF). We have compared the performance of the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus in a series of 544 patients with primary or secondary MF aged ≤ 70 years at the time of diagnosis. The median projected survival of the overall series was 9.46 years (95% confidence interval 7.44-10.59). Median survival for the highest risk groups was less than 4 years in the three prognostic models. By contrast, the projected survival for patients in the intermediate-2 categories by the IPSS, DIPSS, and DIPSS-plus was 6.6, 5.6, and 6.5 years, respectively. The number of patients in the intermediate-2 and high-risk categories was smaller in the DIPSS than in the IPSS or the DIPSS-plus. The IPSS and DIPSS-plus were the best models to discriminate between the intermediate-1 and intermediate-2 risk categories, which is a critical cut-off point for patient selection to transplant. Among patients assigned at diagnosis to the intermediate-2 or high-risk groups by the IPSS, DIPSS, and DIPSS-plus, only 17, 21, and 20%, respectively, were subsequently transplanted. In conclusion, in our contemporary series of younger MF patients only the highest risk categories of the current prognostication systems have a median survival below the 5-year threshold recommended for considering transplantation. Patient selection for transplantation can significantly differ depending on which prognostication model is used for disease risk stratification.

Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia.

The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow-up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2-0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9-4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-mutated patients. Next generation sequencing of 51 genes at the time of transformation showed additional mutations (median number: 3; range: 1-5) in 25 out of 29 (86%) assessable cases. Mutations (median: 1; range: 1-3) were detected in 67% of paired samples from the chronic phase. Leukaemia appeared in a JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival.

Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21-0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate-1 risk.

Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.

To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR4, MR4.5, and MR5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR3. At the last follow-up, response was MR3, MR4, MR4.5, and MR5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

Socioeconomic burden of participation in clinical trials in patients with myeloproliferative neoplasms.

OBJECTIVE: To determine the financial and psycho-social impact of participation in clinical trials of patients with BCR/ABL-negative myeloproliferative neoplasms (MPN). METHODS: An international, observational cross-sectional study was performed in 143 consecutive MPN patients (51% myelofibrosis, 36% polycythemia vera, 13% essential thrombocythemia), 68% from Italy, 17% from USA, and 15% from Spain. RESULTS: Thirty-five percent of patients reported having spent more money during the trial than in previous treatments and 21% having missed more workdays. Twelve percent replied that they would not have participated in the trial if the financial consequences would have been known beforehand. In 10% of the patients, the interpersonal relationships were more affected during the trial than in previous treatment but, overall, 91% subjects believed that participating in the clinical trial was worth the financial or emotional suffering. Concerning patients' suggestions, 54% of them indicated that the number of visits required for the trial should be clearly specified in the informed consent, 60% recommended travel cost reimbursement, and 23% hotel cost reimbursement. CONCLUSIONS: Physicians and pharmaceutical companies involved in clinical trials with patients with hematological diseases should be aware of these problems and make efforts to attenuate the socioeconomic burden of participation in the trials.

Multidimensional assessment of patient condition and mutational analysis in peripheral blood, as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS group.

The International Prognostic Scoring System and its revised form (IPSS-R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS-R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006-2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS-R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next-generation sequencing). The change in likelihood-ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS-R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96-4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56-4.46, P < 0.001). Non-leukemic death was strongly linked to patient condition (HR 2.71, 1.72-4.25, P < 0.001), but not to IPSS-R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease-modifying therapy, evaluated as a time-dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS-R.