Genital chronic graft-versus-host disease: an unmet need that requires trained gynecologists.

OBJECTIVE: Menopause and chronic graft-versus-host disease (cGvHD) are the leading causes of morbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT). Genitalia are one of the target organs of cGvHD causing sexual dysfunction and local symptoms, which may impair women's quality of life. The aim of this study is to describe the prevalence and clinical characteristics of genital cGvHD. METHODS: A retrospective cross-sectional observational study was performed including 85 women with alloHSCT. All women were diagnosed and counseled by a trained gynecologist. Health-related quality of life was assessed by the Cervantes Short-Form Scale and sexual function was evaluated by the Female Sexual Function Index. RESULTS: Seventeen women (20%) included in the study were diagnosed with genital cGvHD. The main complaints were vulvovaginal dryness (42.2%) and dyspareunia (29.4%), the presence of erythema/erythematous plaques (52.9%) being the most frequent sign. Median time from transplant to diagnosis of genital cGvHD was 17 months among those with mild involvement, 25 months for moderate and 42 months for severe forms. Mortality was 29.4% in patients who developed cGvHD with genital involvement versus 8.8% among those without (p = 0.012). CONCLUSION: Early gynecological evaluation might allow to identify patients with mild forms of genital cGvHD, potentially enabling better management and improved outcomes.

High rate of long-term survival for high-risk lymphoma patients treated with hematopoietic stem cell transplantation as consolidation or salvage therapy.

Patients with high-relapse-risk lymphomas or those relapsing after initial therapy have a limited probability of cure with conventional treatment. There is recent inconclusive evidence that, in such cases, intensification or salvage treatment with high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT) increases the response rate and may improve survival. Nevertheless, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 101 consecutive patients receiving high-dose chemotherapy followed by HSCT after induction with standard chemotherapy. The median age was 38 years (range, 12-63 years). The diagnoses were Hodgkin's disease (n = 32), follicular lymphoma (n = 33), diffuse large B-cell lymphoma (n = 12), mantle cell lymphoma (n = 7), T-cell lymphoma (n = 14), and others (n = 3). Patients received either an autologous graft (n = 72) in first complete remission (1CR; n = 23) or in advanced stages (AS; n = 49), or an allogeneic graft (n = 29) in 1CR (n = 7) or in AS (n = 22). We concluded that transplant-related mortality was 2.7% for patients receiving an autologous HSCT and 27% for patients receiving an allogeneic HSCT. The main etiologies were graft-versus-host disease and infection in the allogeneic setting, and infection in the autologous setting. The probability of long-term (12-year) overall survival was 71%, higher than that described for high-relapse-risk lymphoma patients treated without HSCT and significantly better (P < .05) for patients who received the transplant in 1CR (89%) than in AS (65%). Finally, the probability of long-term survival was significantly better for patients treated with HSCT during the period from 2000-2007 (85%) compared with the period from 1989-1999 (72%).

[Consensus opinion on antifungal prophylaxis in haematologic patients: Results of the PROMIC project]. / Posicionamiento y actitudes de manejo sobre la profilaxis antifúngica en el paciente hematológico (proyecto PROMIC).

OBJECTIVE: Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management. METHODS: A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology. RESULTS: Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous. CONCLUSIONS: A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention.

Evaluation of readmissions in hematopoietic stem cell transplant recipients.

BACKGROUND: There is a lack of information on health expenses caused by readmissions among hematopoietic stem cell transplant (HSCT) recipients. We analyzed the rate, causes, and evolution of hospitalization after HSCT. METHODS: We retrospectively studied 140 consecutive patients who received an autologous HSCT (n = 107; 76.4%) or an allogeneic HSCT (n = 33; 23.6%) in our institution from May 2001 through September 2004. RESULTS: There were 45 readmissions in 28 patients (20%): three (10%) in the autologous and 25 (90%), in the allogeneic HSCT cohorts. The overall median age was 35.3 +/- 13.5 years and 54% were women. Hematologic diseases were: multiple myeloma (n = 1, 4%), myelodysplastic syndrome (n = 2, 7%), acute lymphoblastic leukemia (n = 2, 7%), aplastic anemia (n = 2, 7%), chronic myeloid leukemia (n = 3, 11%), non-Hodgkin's lymphoma (n = 4, 14%), Hodgkin's disease (n = 4, 14%) and acute nonlymphoblastic leukemia (n = 10, 38%). The length of stay for each readmission was 25 +/- 21 days. The median day of readmission was +62.5 (range = +19 to +987); however, 75% occurred between days +30 and +70. The causes of hospitalization were: infections (n = 24, 54%), due to the graft (n = 14, 31%), graft failure (n = 4, 9%), coagulation disorders (n = 2, 4%), and second neoplasm (n = 1, 2%). Mortality due to the transplant was 10 patients (14%) including: graft-versus-host disease (n = 3), sepsis (n = 3), thrombotic thrombocytopenic purpura (n = 1), and relapse (n = 3). CONCLUSIONS: Although there was a frequent use of hospital resources (20%) after HSCT with patients hospitalized for a median of 25 days, it was beneficial since there were 86% survivors at 36 months follow-up.

Generation of LAK cells in vitro in patients with acute leukemia.

The in vitro stimulation of lymphocytes with interleukin-2 (IL-2) generates lymphokine-activated killer (LAK) cells with tumoricidal potential. In this work we studied the cytolytic capacity of LAK cells in 51 acute leukemia patients in complete remission (CR) after chemotherapy (CT), in 24 acute leukemia patients who had undergone autologous bone marrow transplantation (ABMT), and in a control group of 44 normal donors. In the normal donor control group the effect of non-IL-2-activated peripheral blood mononuclear cells (PBMC) against blast cells was always lower than 10% lysis, which we have taken as a lower limit for positive results. In 95% of post-CT patients, the lytic effect of PBMC was negative. LAK cells produced positive results in 82% of normal donors and in 37.5% of post-CT patients. The effect of PBMC against K562, i.e. natural killer (NK) activity, in post-CT patients as well as in post-ABMT patients was reduced in comparison with the average for normal donors. LAK cells from 25% of post-CT patients had no notable activity against K562 or Raji, nor was there any positive effect against autologous blast cells. In the rest (75%), one-half generated positive activity. We did not observe any correlation between lytic activity in PBMCs or in LAK cells, nor did we observe significant differences between lytic activity in patients with acute lymphoblastic leukemia (ALL) and those with acute myeloblastic leukemia (AML), or between patients who had undergone CT and those receiving ABMTs. These results support the use of IL-2 as a treatment against minimal residual leukemia.

Hemopoietic stem cell transplantation in childhood: reduction in mortality and improvement of survival over the years.

Stem cell transplantation (SCT) is an effective treatment for life-threatening hematologic and nonhematologic pediatric diseases. Reducing transplant-related mortality (TRM), a major complication of SCT, to improve long-term survival, therefore, is one of the main objectives of transplantation teams. We analyzed TRM and overall survival (OS) over the years in children undergoing SCT in our center. From June 1998 to October 2002, 156 consecutive children, 105 boys and 51 girls, median age 10 years (range, 2-18), with different diagnoses underwent SCT (100 autologous and 56 allogeneic). OS and TRM were analyzed in 2 different periods (June 1989-December 1998 and January 1999-October 2002) and grouped according to the different SCT modalities. The median follow-up was 18 months (range, 1-160). Autologous TRM showed a statistically significant improvement within 1999-2002 (0%) compared with 1989-1998 (12.2%) (P < .05). There were no statistical differences for allogeneic SCT. OS was 34% in the first period and 80.4% in the second period (P < .01), the improvement being for both autologous and allogeneic SCT. In our study, TRM decreased significantly for those children receiving autologous SCT in recent years. OS was significantly better in the latter period (1999-2002), both globally and for each SCT modality.

Mortality of Oncohematological Patients Undergoing Hematopoietic Stem Cell Transplantation Admitted to the Intensive Care Unit.

BACKGROUND: Both autologous and allogenic hematopoietic stem cell transplantation (HSCT) are potentially curative treatments for hematological malignancies. Patients with related complications may need admission to the intensive care unit (ICU) for specific therapy and organ support. A consensus on treatment between hematologists and intensive care specialists is essential. METHODS: This observasional, retrospective study included all recipients of HSCT in a third-level hospital during 2013 and 2014. Certain parameters were taken into account for patients who needed to be admitted to the ICU, evolution, and ICU and hospital mortality. RESULTS: A total of 228 HSCT were carried out: 127 autologous (55.7%) and 101 allogenic (44.3%). Twenty-four patients were admitted to the ICU; 22 had received allogenic HSCT and 2 autologous. The main underlying conditions were acute leukemias (41.6%) and myelodysplastic syndromes (20.8%). Of these patients, 45.8% were in complete remission and 33.3% were in relapse or progression. Causes of admission to the ICU were mainly respiratory failure (70.8%) followed by shock requiring vasoactive drugs. High values for severity scores were observed for APACHE II 25 (19-28) and SOFA 10 (8-14). During hospitalization, a high percentage of patients had hemodynamic (91.7%), renal (87.5%), hepatic (79.2%), and respiratory (87.5%) failure. Mortality in the ICU was 83.3% and hospitalary, 91.7%. All patients requiring invasive mechanical ventilation died in the ICU. CONCLUSIONS: Of recipient patients of allogenic HSCT, 21.8% were admitted to the ICU, presenting a mortality rate of >95%. The main reason for admission was respiratory failure with requirement of invasive mechanical ventilation. Patients with autologous HSCT presented very few complications needing organ support.

Fungal and viral infections after allogeneic hematopoietic transplantation from unrelated donors in adults: improving outcomes over time.

Umbilical cord blood (CB) is increasingly used as an alternative source of stem cells in adult unrelated transplantation. Although registry studies report similar overall outcomes in comparison with BM/PB, comparative studies focusing on severe infections and infection-RM (IRM) with a long follow-up are scarce. A total of 434 consecutive unrelated transplants (1997-2009) were retrospectively analyzed to compare overall outcomes, incidence and risk factors of severe viral and invasive fungal infections in CB (n=65) vs BM/PB recipients (n=369). The 5-year OS was 38 vs 43%, respectively (P=0.2). CB transplantation (CBT) was associated with a higher risk of invasive aspergillosis (100-days-cumulative incidence 16 vs 6%, P=0.04) and CMV infection without differences in RM. No statistically significant differences were found regarding NRM (NRM of 38% in CB vs 37% in BM/PB at 1 year) nor IRM (30% in CB vs 27% in BM/PB at 1 year). In the overall population, NRM and IRM improved in more recent years. In adults who receive a single CBT, the risk of severe infections is increased when compared with unrelated BM/PB recipients, but mortality from infections is similar, leading to similar NRM and survival.

Reversal of severe hepatic veno-occlusive disease by combined plasma exchange and rt-PA treatment.

We report the successful treatment of a case of severe hepatic veno-occlusive disease (VOD) by combined treatment with exchange plasmapheresis and fibrinolysis with rt-PA. Very advanced alterations of hepatic vascular circulation, evaluated by Doppler sonography, reverted to normal after treatment. Severe VOD, defined by McDonald's criteria, produces a mortality of 98%. This case suggests that this new method of combined treatment might contribute to changing the usually bad prognosis of this clinical condition.

Allogeneic transplantation of CD34+-selected cells from peripheral blood in patients with myeloid malignancies in early phase: a case control comparison with unmodified peripheral blood transplantation.

An allogeneic transplantation of CD34(+)-selected cells from peripheral blood (allo-PBT/CD34(+)) from HLA-identical sibling donors was performed in 50 adult patients with acute myeloid leukemia in first complete remission (AML CR1) (n = 29), myelodysplastic syndrome (MDS) (n = 4), or chronic myeloid leukemia in first chronic phase (CML CP1) (n = 17). Clinical results were compared to a concurrent group of 50 patients transplanted with unmodified peripheral blood progenitor cells (allo-PBT), matched for age, diagnosis, and disease stage. The median follow-up period was 29 months (range 1-69). The actuarial probability of developing acute GVHD clinical grade II to IV was 16% (95%CI: 6-26) for the allo-PBT/CD34(+) group and 41% (95%CI: 29-57) for the allo-PBT group (P = 0.002). The actuarial probability of developing extensive chronic GVHD was 22% (95%CI: 8-36) for the allo-PBT/CD34(+) group and 47% (95%CI: 31-63) for the allo-PBT group (P = 0.02). Recipients of allo-PBT/CD34(+) had less toxicity associated with the transplant and better Karnofsky index at the last follow-up. For AML/MDS patients, the actuarial probability of disease-free survival (DFS) for recipients of allo-PBT/CD34(+) and allo-PBT was 65% (95%CI: 45-85) vs43% (95%CI: 28-58) (P = 0.05), respectively. These data provide a rationale for a randomised trial of allo-PBT/CD34(+) vs allo-PBT in AML/MDS patients in early stage of the disease.

Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Spanish Group of Allo-PBT.

A Spanish National PBPC Donor Registry has recently been established for short- and long-term safety data collection in normal donors receiving rhG-CSF. To date, 466 donors have been included in the Registry. Median (range) dose and duration of rhG-CSF administration was 10 microg/kg/day (4-20) and 5 days (4-8), respectively. Donors underwent a median of two aphereses (range, 1-5). Adverse effects consisted mainly of bone pain (90.2%), headache (16.9%) and fever (6. 1%), but no donor discontinued rhG-CSF prematurely due to toxicity. Side-effects were more frequent in donors receiving >10 microg/kg/day than in those with lower doses (82.8% vs 61.8%; P = 0. 004). A significant decrease between baseline and post-apheresis platelet counts was the most important analytical finding (229 x 10(9)/l vs 140 x 10(9)/l; P < 0.0001), with a progressive reduction in platelet count with each apheresis procedure. One donor developed pneumothorax that required hospitalization due to central venous line placement. The mean CD34+ cell dose collected was 6.9 x 10(6)/kg (range, 1.3-36), with only 14 donors (2.9%) not achieving a minimum target of CD34+ cells of 2 x 10(6)/kg. No definitive information about potential long-term side effects is yet available. However, we hope this National Registry will serve as a useful basis for better monitoring of the efficiency and side-effects of cytokine administration in healthy people.

Hemopoietic stem cell transplantation in refractory rheumatoid arthritis is not a contraindication for reconstructive surgery.

Hemopoietic stem cell transplantation (HCST) is an experimental therapy that may produce prolonged remissions in patients with rheumatoid arthritis (RA) resistant to other treatments. Prosthetic articular replacement is often required in severe long-lasting disease. There is a well-founded concern regarding the feasibility and safety of reconstructive surgery after HSCT and as yet no published data on the subject. We report a patient with RA of 9 years' duration resistant to conventional treatments plus femoral head necrosis, who underwent prosthetic hip replacement with no post-surgical complications one year after HSCT, with a sustained response.

Improvement over the years of long-term survival in high-risk lymphoma patients treated with hematopoietic stem cell transplantation as consolidation or salvage therapy.

The role of hemopoietic stem cell transplantation (HSCT) is not well established in certain types of lymphoma, such as those with a high relapse risk or relapsing after initial therapy. New chemotherapeutic schemes and immunotherapy have improved survival of these patients. Nevertheless, there is not enough evidence regarding whether transplantation is the best therapeutic approach. Moreover, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 177 consecutive patients diagnosed with a high risk of relapse or with relapsed lymphoma who underwent HSCT after induction with standard chemotherapy in a tertiary academic center from 1989 to 2013. The median age was 40 years. Diagnoses were Hodgkin disease (n = 56), diffuse large B-cell lymphoma (n = 44), follicular lymphoma (n = 29), mantle cell lymphoma (n = 15), T-cell lymphoma (n = 18), and others (n = 15). Patients received either an autologous graft (n = 154) in first complete remission (1CR; n = 59) or more advanced stages (AS; n = 95), or an allogeneic graft (n = 23) in 1CR (n = 4) or AS (n = 19). In the autologous group, overall survival (OS) at 5 years was 57% and 75% in the periods 1989-2001 and 2002-2013, respectively (P = .05). Patients receiving an allogeneic graft presented an OS of 25% and 43% in the 2 periods. With a mean follow-up of 5 years (95% confidence interval 3.5-6.6), for patients receiving a transplant in 1CR, OS at 5 years was 80%, and for those receiving a transplant in AS it was 59% (P = .003). Nonrelapse mortality (NRM) at 5 years was 3.1% in the autologous group and 27.9% in the allogeneic group (P < .001). The main cause of NRM was infection (44%) in the whole cohort. All this leads to the conclusion that transplantation, as a therapeutic strategy, has shown a high long-term OS in this subgroup of patients with such a poor prognosis. OS improved over the years and reaching 1CR was a good prognostic feature. Infections were the main cause of NRM.

A variant in IRF3 impacts on the clinical outcome of AML patients submitted to Allo-SCT.

Allo-SCT has a strong curative potential for AML patients mainly due to a GVL effect. Unfortunately, GvL and GVHD are intimately linked. IFN regulatory factor-3 (IRF3), by modulating innate immune reactions, could impact on the incidence and intensity of GVL and GVHD. We analyzed two gene variants in IRF3 (rs7251 and rs2304205) on the clinical outcome of 249 AML patients submitted to HLA-identical sibling allo-SCT. Patients with a donor carrying the dominant GG gene variant in rs7251 had, as compared with GC and CC variants, a lower acute GVHD (aGVHD) III-IV incidence (4% vs 11% vs 27%; P=0.0078), a higher relapse incidence (49% vs 35% vs 26%; P=0.018), and lower TRM (7% vs 24% vs 18%; P=0.0065). In functional studies, the GG variant was associated with lower production of IFN-γ, decreased lymphocyte proliferation after antigen presentation by DCs, and lower cytotoxic response of mature natural killer cells. Patients carrying the AA dominant variant in rs2304205 had higher relapse incidence (50% vs 39% vs 18%, P=0.0068). The presence of both variants (GG in rs7251 and AA in rs2304205) in donors and patients resulted in a stronger clinical impact.

Long-term follow-up of HCV-infected hematopoietic SCT patients and effects of antiviral therapy.

This prospective study was initiated in 1993 with the aim to study late effects and responses to antiviral therapy in a cohort of hepatitis C virus (HCV)-infected patients. A total of 195 patients were included from 12 centers. In all, 134 patients had undergone allogeneic and 61 autologous hematopoietic SCT (HSCT). The median follow-up from HSCT is currently 16.8 years and the maximum 27.2 years. Overall 33 of 195 patients have died of which 6 died from liver complications. The survival probability was 81.6% and the cumulative incidence for death in liver complications was 6.1% at 20 years after HSCT. The cumulative incidence of severe liver complications (death from liver failure, cirrhosis and liver transplantation) was 11.7% at 20 years after HSCT. In all, 85 patients have been treated with IFN; 42 in combination with ribavirin. The sustained response rate was 40%. The rates of severe side effects were comparable to other patient populations and no patient developed significant exacerbations of GVHD. Patients receiving antiviral therapy had a trend toward a decreased risk of severe liver complications (odds ratio=0.33; P=0.058). HCV infection is associated with morbidity and mortality in long-term survivors after HSCT. Antiviral therapy can be given safely and might reduce the risk for severe complications.

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT.

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.