Phototherapy and topical treatments for cutaneous graft vs. host disease in haematopoietic stem cell transplantation patients: a scoping review.

Skin is usually the first and most affected organ involved in graft-versus-host disease (GvHD), and treatment is still a clinical challenge. Although the need for skin-directed treatments such as physical treatments and topical medications are generally agreed on, what the gold standard treatment strategy should be remains open to debate. The aim of this scoping review was to synthesize the current knowledge on the topical and physical treatments of cutaneous GvHD in haematopoietic stem cell transplantation patients and to highlight the best evidence available so as to reduce the gap between 'what is known' and 'what is done' in the clinical practice. Twenty-eight studies were included in this qualitative synthesis. Photo-biomodulation with psoralen was not included in this review. Phototherapy (ultraviolet A or B or narrowband B) was the physical treatment most described in the literature in both acute GvHD and chronic GvHD. Topical calcineurin inhibitors such as tacrolimus ointment and pimecrolimus cream as well as corticosteroid creams such as clobetasol and triamcinolone are mainly used in case of chronic GvHD. In all of the studies included in the review, topical treatments were always associated with systemic therapy. None of the topical interventions identified in our review provided strong evidence supporting its use, and the topical approaches seemed to have an adjuvant role in the treatment of cutaneous GvHD.

Nilotinib in steroid-refractory cGVHD: prospective parallel evaluation of response, according to NIH criteria and exploratory response criteria (GITMO criteria).

We conducted a phase I-II study to evaluate Nilotinib (NIL) safety and pharmacokinetics in 22 SR-cGVHD patients; we also evaluated ORR by using in parallel NIH criteria and an exploratory approach, combining objective improvement (OI) without failure criteria (GITMO criteria). Results: 22 patients were enrolled. After dose escalation up to 600 mg/day, MTD was not reached. Main toxicities were asthenia, headache, nausea, pruritus, cramps, and mild anemia. Mean and median plasma concentrations of NIL (C-NIL) were 817 (SD ± 450) and 773 ng/ml. ORR at 6 months, according to 2005 and 2014 NIH and GITMO criteria were 27.8%, 22.2%, and 55.6% respectively; close correspondence has been observed for ORR, according to 2014 NIH criteria, both assessed in a conventional way and assisted by dedicated software (CROSY). At 48 months OS was 75% while FFS, according to NIH and GITMO criteria, was 30 and 25%. In conclusion the safety profile of NIL and long-term outcome makes NIL an attractive option in SR-cGVHD. Exploratory GITMO criteria could represent an alternative tool for easy response evaluation in patients with prevalent skin and lung involvement, but require validation in a larger population; CROSY software showed excellent reliability in capturing ORR according to the 2014 NIH criteria.

'Real-life' report on the management of chronic GvHD in the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Successful treatment of Acremonium fungemia with voriconazole.

We report two cases of Acremonium fungemia with proven involvement of the skin and probably of the lung in patients who were both undergoing chemotherapy, one for mantle cell lymphoma and the other for acute lymphoblastic leukemia. Both patients failed amphotericin B deoxycholate treatment and were successfully treated with voriconazole with very mild toxicity.

Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation.

The management of invasive aspergillosis in patients with hematological malignancies remains controversial. A major problem is how to manage patients who had invasive aspergillosis during remission induction and consolidation therapy and then undergo SCT. Indeed in these patients the mortality rate related to invasive aspergillosis recurrence remains unacceptably high. We report two cases of patients who underwent remission induction for AML, developed invasive aspergillosis during antifungal prophylaxis with itraconazole, failed amphotericin B deoxycholate and liposomal amphotericin B treatment, were successfully treated with voriconazole and eventually underwent SCT with voriconazole prophylaxis without reactivation of invasive aspergillosis.

Conventional hematopoietic stem cell transplants from identical or alternative donors are feasible in recipients relapsing after an autograft.

BACKGROUND AND OBJECTIVES: The risk of relapse after autologous bone marrow transplantation (ASCT) is high and is related to the type of malignancy and phase of the disease. The outcome for the patient who relapses after an autologous transplant is poor. Some of these patients achieve a remission with conventional chemotherapy, but it is usually short-lasting. Most of them succumb to the original disease. One further therapeutic possibility is an allogeneic transplant which would confer the potential advantage of a graft-versus-leukemia effect in addition to the lack of tumor contamination of the graft and to a high-dose intensity conditioning regimen. DESIGN AND METHODS: We have studied the outcome of 31 patients with hematologic malignancies who underwent an allogeneic hematopoietic stem cell transplant (HSCT) after failing an autologous transplant because of relapse (n=29) or persistent aplasia (n=2). The median age at allograft was 36 years (18-55) and the interval from autograft to allograft was 21 months (3-141). The source of stem-cells was unmanipulated bone marrow (n=26) or growth-factor-mobilized peripheral blood (n=5). The donor was an HLA-identical sibling (n=7), or an alternative donor (n=24) (family mismatched n=11, or matched unrelated n=13). The conditioning regimen was cyclophosphamide and thiotepa (n=22), or cyclophosphamide and total body irradiation (n=9) Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine (CyA) + methotrexate (MTX). RESULTS: Acute GvHD was scored as 0-I, II, or III-IV in 39%, 48%, and 13% of the patients, respectively. Sixteen patients died of transplant-related complications and one of progressive disease. With a median follow-up of 220 days (9-2104) the actuarial 2-year transplant-related mortality (TRM) was 51%, the actuarial relapse risk 37%, the actuarial survival 46%. Fifteen patients (48%) are alive in complete remission, with a median follow-up of 32 months (range 2-71). INTERPRETATION AND CONCLUSIONS: These data suggest that patients relapsing after an autotransplant should be screened for potential related or unrelated donors: although TRM remains high there is a definite chance of long-term disease-free survival if these patients are allografted.

Quality of life in 244 recipients of allogeneic bone marrow transplantation.

The number of long-term survivors after allogeneic bone marrow transplantation (BMT) has been increasing over the past years, and quality of life (QOL) has become an important end-point. We studied 244 patients undergoing an allogeneic BMT to identify factors and events influencing psychosocial outcome. Patients enrolled received the Psychosocial Adjustment to Illness Scale (PAIS) questionnaire assessing psychological and social adjustment to chronic illness or its sequelae. Eighty-two per cent of patients had a haematological disease. The median age was 28 years at BMT, and the median follow-up was 61 months. The median overall PAIS score for all patients was 56 (range 22-76): 25% (n = 61) of patients were considered to have a good QOL ( 75 percentile score). Factors associated with a poor QOL in multivariate analysis were: patients' age at BMT (> 25 years, P < 0.01); presence of long-term sequelae (P < 0.01); chronic graft-versus-host disease (GVHD) (P < 0.05); and a short interval from BMT (< 5 years; P < 0.05). The QOL improved with time: 12% of patients reported a good QOL within 5 years compared with 38% after this time point and, conversely, 38% reported a poor QOL within 5 years compared with 24% after this time point (P < 0. 0001). Older patients had significantly poorer QOL compared with younger patients (< or = 25 years; P = 0.01). Females had significantly poorer scores when compared with males in the sexual (P < 0.0001) and psychological domains (P = 0.001). The data suggest that (i) one-third of patients undergoing allogeneic BMT report a poor QOL; (ii) factors associated with poor QOL are older age, presence of long-term sequelae, chronic GVHD and short follow-up; (iii) QOL is superior in long-term survivors; and (iv) BMT affects different aspects of life in males and females. A longitudinal study is ongoing to prove the effect of time on quality of life.

Reduced intensity thiotepa-cyclophosphamide conditioning for allogeneic haemopoietic stem cell transplants (HSCT) in patients up to 60 years of age.

UNLABELLED: Transplant-related mortality (TRM) remains a major problem in older patients undergoing allogeneic haemopoietic stem cell transplants (HSCTs). We have therefore explored a less intensive conditioning in 33 patients with a median age of 52 years (range 43-60) transplanted from human leucocyte antigen (HLA)-identical siblings. The underlying disease was chronic myeloid leukaemia (n = 15), acute myeloid leukaemia (n = 6), myelodysplasia (n = 7) or a chronic lymphoproliferative disorder (n = 5); 15 patients (45%) had advanced disease. The regimen consisted of thiotepa (THIO; 10 mg/kg) on day -5 and cyclophosphamide (CY; 50 mg/kg) on days -3 and -2 (total dose 100 mg/kg). The source was bone marrow (BM) (n = 17) or granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) (n = 16), which were infused without manipulation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A (CyA) and a short course of methotrexate. Mean time to achieve a neutrophil count of 0.5 x 109/l was 17 d (range 11-23) and full donor chimaerism was detected in 79% of patients by day 100. Acute GVHD grade III or IV occurred in 3% of patients. Chronic GVHD was seen in 45% of patients, with a significant difference for PB (69%) compared with BM transplants (23%) (P = 0.009). For BM grafts, the actuarial 2-year TRM was 6%, the relapse 56% and survival 87%; for PB grafts, these figures were, respectively, 27%, 33% and 68%. Twenty-five patients are alive at a median follow-up of 762 d (range 216-1615) and 20 patients (60%) remain free of disease. Thirteen patients (39%) received donor lymphocyte infusion (DLI) either for persisting or relapsing disease and six patients had complete remission. IN CONCLUSION: (i) patients up to the age of 60 years can be allografted with reduced intensity conditioning; (ii) the procedure was associated with a low transplant-related mortality, particularly for bone marrow grafts, because of a lower risk of chronic GVHD; and (iii) DLI were required after transplant in half the patients for persisting disease or relapse.

Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study.

This is a dose-finding study using foscarnet for CMV prophylaxis after allogeneic bone marrow transplantation (BMT) in 20 high risk patients (unrelated donors, or T cell depleted, and/or advanced disease). Foscarnet was started on day +1 after BMT and continued until day +100. We explored four different dose levels, patients being entered at the lowest dose level until one patient experiences CMV-reactivation, identified as two consecutive positive CMV antigenemias (CMVAg-emia). The four dose levels expressed as mg/kg/day between days 1 and 30 (induction) and between days 31 and 100 (maintenance) were respectively: dose level I = 60/30 (n = 5); dose level II = 120/60 (n = 4); dose level III = 120/90 (n = 5) and dose level IV = 120/120 (n = 6). All patients showed engraftment: PMN > or =0.5 x 109/l at a median interval of 16, 21, 17, 15 days after BMT, and Plt > or =30x10(9)/l on days 19, 16, 17, 17 respectively. CMVAg-emia was seen in 10 patients at a median interval of 53 days post-BMT (range 33-89) with a median of 10 CMV antigen+ cells (range 1-16). There was a dose effect of foscarnet on CMVAg-emia: respectively 4/5 patients (80%), 2/4 (50%), 3/5 (60%) and 1/6 (18%) at dose levels I, II, III, IV (P = 0.1). CMV disease was seen in 3/9 (33%) at dose levels I, II and 0/11 at dose levels III, IV (P = 0. 07). The median number of CMV antigen-positive cells at diagnosis of CMV infection was different: 13 in dose levels I-II and two in dose levels III-IV (P = 0.01). Increased creatininine was seen in 15 patients with a mean of 1.8 mg% (range 1.5-5.7) and was the cause of discontinuation in nine patients (45%). Renal toxicity was reversible in all nine patients. Overall actuarial TRM at 2 years was 31%: 47% for patients at dose levels I-II and 19% for patients at dose levels III-IV. In conclusion, foscarnet exhibits a dose-dependent prophylactic effect on CMVAg-emia, CMV disease and transplant-related mortality with acceptable and reversible renal toxicity.

Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.

BACKGROUND AND OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of the hemopoietic stem cell (HSC) characterized by intravascular hemolysis and increased risk of venous thrombosis. There are different therapeutic approaches for PNH which do not cure the disease, but can decrease its complications. Allogeneic bone marrow transplantation (BMT) may cure PNH. We reports here our experience of seven PNH patients who underwent allogeneic BMT. DESIGN AND METHODS: Between January 1991 and January 1999 seven patients with PNH, aged 23 to 37, were transplanted with unmanipulated bone marrow from HLA identical siblings. Median time from diagnosis to BMT was 2.5 years (range: 1-16). All patients were transfusion-dependent and had received various treatments before BMT: steroids, vitamins, cyclosporin A (CyA), growth factors. One patient had also been treated with anti-thymocyte globulin. One patient was HbsAg positive and one anti-HCV positive. At the time of BMT the median value of hemoglobin (Hb) was 9 g/dL (range 6.5-11), white blood cells 5&10(9)/L (range: 2.9-7.7), platelets 97&10(9)/L (range: 31-355), LDH: 2726 U/L. The conditioning regimen was cyclophosphamide (160 mg/kg) and busulfan (10-14 mg/kg), followed by unmanipulated bone marrow (median of 5&10(8) cells/kg) and CyA (+MTX in two patients) for prophylaxis of graft-versus-host disease (GvHD). RESULTS: All seven patients are alive, full chimeras, with complete hematologic recovery and no evidence of PNH, at a median follow up of 51 months post-BMT (6-103). Time to achieve a granulocyte count of 0.5&10(9)/L, platelets 30&10(9)/L and Hb 10 g/dL was respectively 16, 19 and 22 days. Acute GvHD was limited or mild in six patients, and severe in one. Chronic GvHD was extensive in two patients. INTERPRETATION AND CONCLUSIONS: This study confirms that HLA identical sibling BMT is an effective therapeutic option for PNH, also in the hemolytic phase of the disease: it also suggests that HBV and HCV infections are not an absolute contraindication.

The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on the risk of relapse in patients with acute myeloid leukaemia undergoing allogeneic bone marrow transplantation.

One hundred and fifty acute myeloid leukaemia (AML) patients in first remission received an allogeneic bone marrow transplant (BMT), after conditioning with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 3.3 Gy x 3 (total nominal dose 9.9). The received dose, as recorded by thermoluminescent dosimeters, ranged between 7. 83 and 12.25 Gy. Patients who received TBI < 9.9 Gy (n = 34) had a significantly higher relapse rate when compared with patients receiving >/= 9.9 Gy (n = 116) (43% vs. 19%; P = 0.002). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A (CyA) with or without methotrexate (MTX). The dose of CyA was either 1 or 5 mg/kg/day i.v. from day -1 to + 20, then 10 mg/kg/day orally until day + 365. Patients receiving 5 mg/kg CyA (n = 40) had a higher risk of relapse (49% vs. 15%; P = 0.0001). Thus, low-dose TBI (< 9.9 Gy) and high-dose CyA (5 mg/kg) were significant predictors of leukaemia relapse. Patients were then divided into three groups: those who had both negative predictors (< 9.9 Gy TBI and 5 mg/kg CyA; n = 26); those who had only one (either < 9.9 Gy TBI or 5 mg/kg CyA; n = 22); and those who had neither (>/= 9.9 Gy TBI and 1 mg/kg CyA; n = 102). The three groups were comparable for FAB subtype, interval diagnosis transplant and age. The 5-year actuarial relapse rate for these three groups of patients was 49%, 41% and 15%, with no difference between the first two and a significant difference when compared with the latter (P < 0.01). These data indicate that acute myeloid leukaemia can be cured with allogeneic bone marrow transplantation given an intensive conditioning regimen and low-dose immunosuppression post-graft. Either alone is insufficient to produce long-term disease-free survival. These results may be relevant for programmes of reduced intensity conditioning designed for patients with acute leukaemia.

Antigen detection in the diagnosis and management of a patient with probable cerebral aspergillosis treated with voriconazole.

This report describes the diagnosis and management of a 16-year-old boy who developed neurological signs and symptoms suggestive of cerebral aspergillosis following a haploidentical bone marrow transplant. A new sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of Aspergillus galactomannan circulating antigens (Platelia Aspergillus, Sanofi Diagnostic Pasteur, France) was used on serum and cerebrospinal fluid to obtain a presumptive diagnosis and to monitor the course of the disease. Having failed conventional therapy with amphotericin B, the patient received compassionate treatment with voriconazole for a period of 37 days. High levels of voriconazole were observed in both serum and cerebrospinal fluid (CSF), with a trend toward accumulation. After 7 days a marked improvement in the patient's neurological symptoms was noted, and ELISA data indicated a corresponding decrease in Aspergillus galactomannan levels in both serum and CSF. Voriconazole was well tolerated, with only transient increases in ALT/AST recorded during therapy. Although the patient survived the acute Aspergillus infection, he subsequently died of an unrelated infection.

Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin.

Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications.