The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.

We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/µl vs 38±8 x103 cells/µl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other.

Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-ß.

OBJECTIVE: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx. METHODS AND RESULTS: We present two cGVHD cases of oropharyngeal fibrotic changes that affected functions that were treated with photobiomodulation (PBM) therapy. These case reports suggest that PBM therapy represents an additional, innovative approach affecting discrete phases in cGVHD-associated fibrotic changes. CONCLUSIONS: We discuss these observations in the context of currently understood molecular mechanisms, especially induction of transforming growth factor beta and NFκB that appear to be counter-intuitive to their known roles in matrix synthesis and inflammation that contribute to tissue fibroses. The clinical benefit noted in the two cases presented clearly indicates that there are distinct mechanistic and biological insights in the regulation of these molecular pathways in determining therapeutic efficacy with PBM therapy.

Successful management of Mycobacterium haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

Nontuberculous mycobacterial infections can often occur in individuals with adequate immune function. Such infections typically have cutaneous involvement and are caused by rapidly growing mycobacterium. Other nontuberculous mycobacteria species, like Mycobacterium haemophilum, almost always present as opportunistic infections occurring in severely immunocompromised hosts. Here, we present a complicated and protracted course of diagnosing M. haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center.

INTRODUCTION:: Allogeneic hematopoietic stem cell transplantation (ASCT) representes a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT. METHOD:: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05. RESULTS:: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p<0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165). CONCLUSION:: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients.

Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center / Resultados do transplante alogênico de células-tronco em doentes com leucemia mieloide aguda com doença ativa: experiência de um único Centro Oncológico Europeu

Summary Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) representes a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT. Method: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05. Results: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p<0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165). Conclusion: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients.

Resumo Introdução: o transplante alogênico de células-tronco hematopoiéticas (TCTH-alo) representa uma abordagem potencialmente curativa para pacientes com leucemia mieloide aguda (LMA) recorrente ou refratária. Nosso trabalho apresenta o resultado de pacientes com recaída ou doença refratária tratados com TCTH-alo. Método: coorte retrospectiva incluindo 61 pacientes de 1994 a 2013 com diagnóstico de recidiva/LMA refratária. Os desfechos de interesse foram mortalidade relacionada ao transplante (MRT), incidência da doença aguda e crônica do enxerto contra hospedeiro (DECH), incidência de recaídas, sobrevida livre de progressão (PFS - progression-free survival) e sobrevida global (SG). A significância estatística foi considerada para p<0,05. Resultados: a média de idade foi de 61 anos (variação de 1 a 65). A incidência cumulativa de 90 dias, 1 ano e 3 anos de MRT foram de 60%, 26,7% e 13,3%, respectivamente (p<0,001). A incidência de recaída foi de 21,7% em 1 ano, 13% em 3 anos e 8,7% em 5 anos. A SG mediana foi estimada em 8 meses (IC 95% 3,266-12,734) e a mediana de PFS, em 3 meses (IC 95% 1,835-4,165). Conclusão: em nossa coorte, MRT no primeiro ano após o transplante permanece considerável, mas TCTH-alo nesse cenário parece ser uma boa opção para pacientes com LMA ativa. No entanto, novas abordagens são necessárias para reduzir MRT e recaída nesse conjunto de pacientes.

[The efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

To study the efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 7 cases with FLT3-ITD positive AML have received allo-HSCT in our department from May 2013 to January 2015. Six cases were administrated with sorafenib after hematopoietic reconstruction. Another patient relapsed on day 192 past allo-HSCT, then she started to use sorafenib after remission of re-induction regimens. Five patients survived. The median progression free survival was 280(126-366)day. This study suggests that sorafenib might prevent relapse past allo-HSCT and improve survival in patients with FLT3-ITD positive AML.

Alternative novel therapies for the treatment of elderly acute myeloid leukemia patients.

With a median age at diagnosis of approximately 65-70 years, acute myeloid leukemia (AML) represents a major therapeutic challenge in the elderly. Only 30-35% of elderly patients with AML are considered eligible for intensive chemotherapy and do actually receive it. However, the long-term benefit associated with intensive chemotherapy remains marginal, and the overall outcome for this population remains poor. The remaining 60-65% of elderly AML patients receives supportive care only. Nevertheless, several studies have indicated that patients who receive any therapy had a better outcome if compared with patients who receive supportive care only. Thus, the development of novel, less toxic, targeted agents is offering new options to older AML patients who are unfit for intensive approaches. In the present review, we will report on the results achieved using intensive chemotherapy and novel agents, and will describe some of the new strategies under development for treating older AML patients.

Dermatic Scedosporium apiospermum infection after autologous bone marrow transplantation.

Infection with Scedosporium apiospermum (S. apiospermum) is rare, although it is associated with a high fatality rate, especially in immunosuppressed patients. A 23-year-old man with acute myelogenous leukemia (AML) (M2) who was pretreated with chemotherapy for autologous bone marrow transplantation developed a skin ulcer on the left groin. After a culture study demonstrated the presence of S. apiospermum, voriconazole was administered and the lesion rapidly improved. Since a diagnosis of S. apiospermum continues to depend on the results of a fungal culture and most isolates of S. apiospermum are resistant to amphotericin B, voriconazole should be considered as the first choice when "mold" is thought to be the causative organism.

Enhancing laser thermal-therapy using ultrasound-microbubbles and gold nanorods of in vitro cells.

Gold nanorods (GNRs) are being exploited for their absorption properties to improve thermal therapy. However, a key challenge is delivering sufficient concentration of GNRs to induce a therapeutic effect. In this study, ultrasound and microbubbles (USMBs) were used to enhance intracellular uptake of GNRs. AML-5 cells in suspension (0.6 mL) were exposed to ultrasound (1.3 and 1.7 MPa peak negative pressure) and definity microbubbles (1.7% v/v) for 1 min at varying GNR concentrations (0-2.5×10(11) per mL). Following ultrasound-microbubble treatment, cells were centrifuged twice and treated with an 810 nm laser at an average fluence rate of 3.6 W/cm(2) for 5 min. In addition, cells were incubated with GNRs for 12 h prior to laser treatment. Following the treatment, cell viability (V(PI)) was assessed using propidium iodide (PI) and flow cytometry. Cell viability decreased by ∼4-folds with the combined treatment of USMB+GNR+Laser (V(PI)=17%) compared to cells incubated with GNR+Laser (V(PI)=68%). This effect depended on ultrasound pressure and GNR concentration. Higher cell death was achieved at higher GNR concentration and 1.3 MPa peak negative pressure. Cell viability decreased from 92% to 29% with increasing GNR concentration from 1×10(11) to 1.5×10(11) GNR/mL. In addition, higher temperatures were observed using a thermal camera with the combined treatment (USMB+GNR+Laser) of 59±1°C compared to 54±0.9°C for cells incubated with GNRs. The combined treatment of ultrasound-microbubble and gold nanorod laser induced thermal-therapy improved treatment response of in vitro cells.

Clinical effectiveness of early treatment with hyperbaric oxygen therapy for severe late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation in pediatric patients.

HC is a possible cause of morbidity and extended hospitalization after HSCT. Recent studies have reported the efficiency of HOT in adult patients who underwent allogeneic HSCT, but data in children are scarce. We report our single center experience with HOT in late-onset HC after HSCT. Treatment with HOT consisted of daily sessions of breathing 100% O(2) for a total of 75 min in the hyperbaric chamber with a minimum of eight sessions. HOT had been associated with a concomitant treatment with oral oxybutynin, hyperhydration and/or irrigation of the bladder through the catheter. Cidofovir had been administered based on the demonstration of viral infection. Between 2004 and 2011, 10 patients developed severe HC after a median of 26 days after HSCT. HOT was started after a median of six days since the clinical diagnosis of HC. After a median of 10 sessions of HOT, seven of 10 patients were in complete remission. HOT is a well-tolerated procedure also in the pediatric setting. The early start of HOT might be effective in the treatment of HC offering advantages in terms of duration of symptoms and hospitalization.