Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients.

Pediatric refractory or relapsed acute lymphoblastic leukemia (ALL) poses unique therapeutic challenges, with novel immunotherapy approaches offering potential cure opportunities. In this frame, the use of Blinatumomab may induce durable remissions, serving as a successful bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Herein, we retrospectively summarize the Greek experience on pediatric relapsed/refractory B-cell precursor ALL patients that were treated with Blinatumomab in a compassionate, off-label setting as an effort to achieve disease clearance and proceed to allo-HSCT. In our cohort of 9 patients, 6/9 (66.7%) responded to Blinatumomab, achieving complete morphological remission (CR) after the 1st cycle, while minimal/measurable residual disease (MRD)-negativity (<10-4) after the 1st cycle was achieved in 2/2 patients (100.0%) with prior CR. A successful bridge to HSCT was feasible in 5/9 patients (55.6%). Median relapse-free survival (RFS) was 3.0 months (range 0.5-21.4 months) and median overall survival (OS) was 8.7 months (range 1.4-47.1 months) for the whole pediatric cohort. There was a trend of prolonged survival among patients who achieved MRD response after the 1st Blinatumomab administration. MRD response (defined as the >=2-log reduction of MRD value before and after Blinatumomab administration), was associated with a median RFS/OS of 7.4/7.6 months, while lack of MRD response was associated with a median RFS/OS of 0.5/3.0 months, respectively. Novel therapeutic maneuvers, in order to overcome disease resistance, i.e. increased usage of Blinatumomab dose (45 µg/m2/day), combination with donor lymphocyte infusions (DLIs), use of other immunotherapy salvage approaches (inotuzumabozogamicin), are herein discussed. Additionally, the optimal number of Blinatumomab cycles, the CD19-negative relapses and lineage switch, are also addressed. Our data although referred to a limited, however refractory or relapsed and heavily pretreated number of patients, strongly suggest that Blinatumomab may well induce sustained remissions and serve as an effective bridge to HSCT. Whether immunotherapy combined with chemotherapy can outweigh the need for subsequent allo-HSCT, if incorporated into frontline high-risk ALL therapy, remains an optimistic issue to be verified in future randomized clinical trials.

Infectious complications following allogeneic stem cell transplantation by using anti-thymocyte globulin-based myeloablative conditioning regimens in children with hemoglobinopathies.

BACKGROUND: Anti-thymocyte globulin (ATG) has been used to prevent graft failure/rejection in the setting of allogeneic stem cell transplantation (allo-SCT) for hemoglobinopathies; however, epidemiology data for transplant-related infections in this population are scarce. METHOD: We retrospectively analyzed the epidemiology of bacterial, fungal, viral, and parasitic infections in a cohort of 105 children and adolescents with ß-thalassemia (n = 100) or sickle cell disease (n = 5) who underwent allo-SCT using human leukocyte antigen (HLA)-identical sibling (n = 96) or HLA-compatible unrelated donors (n = 9) in a single institution. All patients received an ATG-based conditioning regimen. RESULTS: The cumulative incidence of cytomegalovirus (CMV) viremia was 45.7% (95% confidence interval [CI] 33-55%), developing at a median of 48 (range 12-142) days without evidence of overt CMV disease. Herpes zoster developed in 8 patients at a median of 12 months post transplant, while 10 patients presented with late onset hemorrhagic cystitis at a median of 35 days post transplant. The cumulative incidence of bacteremia was 17.1% (95% CI 10.6-25%), occurring at a median of 74 (range 24-110) days. No patient developed probable or definite invasive fungal infection. Four deaths were recorded; 2 of them were attributed to infections (toxoplasmosis and Pneumocystis jirovecii pneumonia, respectively). CONCLUSION: The rate of infections after allo-SCT, using an ATG-containing preparative regimen, in our population of pediatric patients with hemoglobinopathies is comparable to that reported elsewhere with the use of non-ATG containing regimens.

Pilot study of 19 patients with severe pemphigus: prophylactic treatment with rituximab does not appear to be beneficial.

AIMS: To assess the efficacy and safety of rituximab in refractory pemphigus and the possible benefit of an additional prophylactic infusion at 6 months. METHODS: Seventeen patients with pemphigus vulgaris, 1 with pemphigus foliaceus and 1 with pemphigus vegetans were treated with 4 weekly infusions of rituximab (375 mg/m(2)). Nine patients received an additional prophylactic infusion after 6 months while the rest received no maintenance therapy. In case of recurrence, an additional single infusion was administered. RESULTS: Control of the disease was obtained after 3-8 weeks. End of the consolidation phase for all patients was observed after 16 weeks. Patients remained in full remission for 7-42 months. All immunosuppressive agents, including prednisone, were discontinued after 2-12 months. The disease relapsed in 5 out of 9 patients who received the additional prophylactic infusion, and in 3 out of 10 patients among those skipping the prophylactic additional infusion. CONCLUSION: One course of rituximab and treatment of relapses is highly effective and well tolerated in the treatment of refractory pemphigus. In this pilot study of 19 patients, the prophylactic infusion does not appear to have provided any additional benefit to the patients receiving it.

Correlation of antibodies against desmogleins 1 and 3 with indirect immunofluorescence and disease status in a Greek population with pemphigus vulgaris.

BACKGROUND: The use of ELISA testing of antibodies to desmogleins 1 and 3 (anti-Dsg1 and anti-Dsg3) and indirect immunofluorescence (IIF) has been strongly supported for the serologic diagnosis of pemphigus. The purpose of this study was to correlate anti-Dsg1 and anti-Dsg3 with IIF values, disease localization, treatment and clinical course in Greek patients with pemphigus vulgaris (PV). METHODS: A total of 54 patients with PV had ELISA serum testing for the presence and titers of anti-Dsg1, anti-Dsg3 and IIF. Anti-Dsg1, anti-Dsg3 and IIF were correlated with treatment and disease localization. For 40 patients, titers of anti-Dsg1 and anti-Dsg3 were assessed in relation to treatment and clinical course after 12 months. RESULTS: Anti-Dsg3 and anti-Dsg1 positivity in patients with negative IIF was 70.6% and 58.8%, respectively. Anti-Dsg1 and anti-Dsg3 were positive in 89.3% and 100% of patients with mucocutaneous disease, respectively, 88.9% and 66.7% of patients with skin limited disease, respectively and 52.9% and 76.5% of patients with mucosal limited disease, respectively. Both antibody titers showed significant correlation with IIF and treatment status. Improvement of clinical status was associated with significant decrease of both anti-Dsg1 and anti-Dsg3 after 12 months. CONCLUSIONS: Serum testing of anti-Dsg1 and anti-Dsg3 in PV patients not only provides significant correlations with IIF, treatment and disease type, but may serve as a monitoring tool for clinical course and treatment guidance.

Effectiveness of topical calcineurin inhibitors as monotherapy or in combination with hydroxychloroquine in cutaneous lupus erythematosus.

BACKGROUND: Calcineurin inhibitors show potent anti-inflammatory effects and favorable safety profile when used in the treatment of cutaneous lupus erythematosus (CLE). OBJECTIVE: The present study investigates the change in clinical parameters of erythema, desquamation and edema, when calcineurin inhibitors are used as monotherapy or in combination with hydroxychloroquine in CLE for a period of 60 days. METHODS: 18 patients were treated with topical tacrolimus and 20 patients with topical pimecrolimus, as monotherapy or in combination with hydroxychloroquine. Clinical parameters of erythema, desquamation and edema were assessed on a scale from 0 to 3 for erythema and edema and 0 to 2 for desquamation. RESULTS: Statistically significant improvement in erythema, desquamation and edema was observed in patients on monotherapy with calcineurin inhibitor and combination treatment with hydroxychloroquine, regardless of disease type. Combination treatment resulted in improvement of edema in 100% of patients, while monotherapy did so in 75% of patients. CONCLUSIONS: Topical calcineurin inhibitors enhance the therapeutic effect of systemic agents in cutaneous lupus erythematosus, and result in improvement of the clinical parameters studied.

The role of inflammatory markers in assessing disease severity and response to treatment in patients with psoriasis treated with etanercept.

BACKGROUND: Psoriasis is a chronic, systemic, inflammatory disease. Inflammatory markers are used in clinical practice to detect acute inflammation, and as markers of treatment response. Etanercept blocks tumour necrosis factor (TNF)-α, which plays a central role in the psoriatic inflammation process. AIM: To reveal any possible association between disease severity [measured by Psoriasis Area and Severity Index (PASI)] and the inflammatory burden (measured by a group of inflammatory markers), before and after etanercept treatment. METHODS: In total, 41 patients with psoriasis vulgaris, eligible for biological treatment with etanercept, were enrolled in the study. A set of inflammatory markers was measured, including levels of white blood cells and neutrophils, fibrinogen, ferritin, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), haptoglobin, ceruloplasmin and α1-antitrypsin, before and after 12 weeks of etanercept 50 mg twice weekly. RESULTS: All markers were reduced after treatment (P < 0.001). PASI correlated with fibrinogen and hs-CRP. Of the 41 patients, 19 (46.3%) achieved reduction of 75% in PASI (PASI75). An increase in hs-CRP and ESR difference (values before minus values after treatment) was related to higher likelihood of achieving PASI75. CONCLUSIONS: Inflammatory markers, particularly hs-CRP and to a lesser extent, fibrinogen and ESR, can be used to assist in assessing disease severity and response to treatment in patients with psoriasis. A combination of selected inflammatory factors (which we term the Index of Psoriasis Inflammation) in combination with PASI might reflect inflammatory status in psoriasis more accurately than each one separately.

Infliximab for the treatment of psoriasis in Greece: 4 years of clinical experience at a single centre.

BACKGROUND: Infliximab, a chimeric monoclonal antibody, has been shown to be effective for moderate to severe psoriasis. Clinical experience with long-term infliximab therapy for psoriasis is accumulating, and it is therefore important to share our experience with its use in real-life clinical practice. OBJECTIVES: To report our experience with infliximab (Remicade; Schering Plough, Kenilworth, NJ, U.S.A.) for the treatment of moderate to severe plaque psoriasis (and/or arthritis) from a single clinic in Greece. PATIENTS AND METHODS: Between August 2004 and March 2008, 62 patients presenting to our clinic with moderate to severe psoriasis were treated with infliximab. Disease phenotype, clinical course, disease severity and adverse events were assessed throughout the treatment period. RESULTS: Infliximab resulted in a reduction of median Psoriasis Area and Severity Index (PASI) of 70% at week 6 and 84.4% at week 14. Nineteen patients who have completed 1 year on infliximab treatment experienced sustained efficacy with a median PASI improvement of 92.16% and a Physician's Global Assessment (PGA) of 'clear' or 'almost clear', while nine patients have reached approximately 20 months of continuous therapy. All patients with psoriatic arthritis showed marked improvement in their clinical symptoms following the first infusion. Eight patients (12.9%) experienced adverse events that required discontinuation of treatment. There were no statistically significant differences in PASI and Dermatology Life Quality Index (DLQI) scores between patients with arthritis and those with only skin lesions, or between those who received methotrexate, either from the beginning or during infliximab therapy, and those who did not receive methotrexate at all. Selected patients of interest are discussed. CONCLUSIONS: The above data confirm previous reports that treatment with infliximab is an efficacious and safe option for patients with moderate to severe plaque psoriasis (and/or arthritis). Long-term follow-up, continued pharmacovigilance, and controlled comparative studies will be required to fully evaluate its use in the treatment of psoriasis.

CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder.

BACKGROUND: CHILD syndrome, a rare hereditary disorder of keratinization (MIM 308050, 300275), is the acronym proposed by Happle to name a rare entity, characterized by congenital hemidysplasia, icthyosiform nevus and limb defects, ranging from digital hypoplasia to icthyosiform nevus and ipsilateral limb defects, ranging from digital hypoplasia to complete amelia. PATIENTS AND METHODS: A 9-month-old female infant presented with skin and limb defects involving the right side of her body. Clinical and laboratory evaluation was performed, including DNA sequence analysis of the NSDHL gene. RESULTS: Our patient presented with some of the typical clinical characteristics of CHILD syndrome, i.e. two large erythematous plaques with sharp borders, covered with yellow, wax-like scaling, on the right axilla and on the right groin, dysplastic right hand and alopecia of the right occipital area. The diagnosis was confirmed by DNA screening analysis, that detected a missense mutation c.314C-->T;p-A105V, in the coding region of the NSDHL gene (exon4) of our patient. CONCLUSIONS: This is the first report of CHILD syndrome ever reported in Greece. We suggest that the diagnosis of the syndrome is important for patient information and genetic counselling.

Sequential treatment with biologics: switching from efalizumab to etanercept in 35 patients with high-need psoriasis.

BACKGROUND: Use of biological agents has been shown to be an efficacious approach in psoriasis, when traditional treatments fail. However, there are limited data on the effectiveness and safety of switching from one biological agent to another. OBJECTIVES: We aimed to evaluate the effectiveness and safety of etanercept as a sequential treatment in patients previously treated with efalizumab, and to evaluate different transition strategies from efalizumab to etanercept. METHODS: We present a retrospective study in patients with high-need plaque psoriasis who were unable to continue efalizumab and were immediately switched to etanercept. RESULTS: We included 35 patients during a 4.5-year period. At 24 weeks of etanercept therapy, 57% of patients had a PASI reduction of 75%, suggesting that alternating between biological agents is feasible. We used three different switching approaches: (i) etanercept in combination with cyclosporine as bridge therapy, (ii) etanercept in combination with methotrexate as bridge therapy, (iii) etanercept monotherapy. Combination therapy was efficacious in all patients, including eight patients with rebound phenomenon with efalizumab. Etanercept was discontinued in two patients as a result of serious adverse events that consisted of an oral squamous cell carcinoma and a diffuse B-cell-non-Hodgkin lymphoma. CONCLUSIONS: In our experience, it seems that etanercept alone may not be sufficient when transitioning from efalizumab in high-need patients with severe worsening or rebound of psoriasis. In such patients, combination of etanercept with cyclosporine or methotrexate is a more effective approach. Non-response to efalizumab did not preclude clinical response after switching to etanercept.

A simple 3-day "rush" venom immunotherapy protocol: documentation of safety.

BACKGROUND: Venom immunotherapy (VIT) is the only effective treatment for hymenoptera hypersensitivity, but conventional protocols require a few weeks. OBJECTIVE: We present the safety of a 3-day "rush" protocol that requires only 7 injections and 255 mgr cumulative dose before the 100 microg maintenance dose. METHODS: Forty-nine patients (33 males, 16 females) of mean age 43.57+/-12.9 yrs received "rush" VIT. Only 7 injections were required until the maintenance dose of 100 mgr was reached on Day 5. On Day 1, four injections were administered with initial dose of 5 mgr and total dose of 75 microg. On Day 3 a cumulative dose of 180 mgr was administered in three injections (40 mgr, 60 mgr and 80 mgr). A dose of 100 mgr was administered on Day 5. Twenty-nine individuals were treated with Honey-Bee venom; 18 with Common wasp; 5 with Paper Wasp; while 13 patients received Mixed Vespid preparation. Inclusion criteria were documented IgE-mediated allergy with intradermal sensitivity to < or =0.1 mgr/ml venom concentration and concomitant detection of specific venom IgE > or =0.35 kU/l. RESULTS: All patients reached the maintenance dose. Forty-nine patients received 65 immunotherapy courses, resulting in 1520 injections. Thirty-three systemic reactions: 7 during building phase (1.5%); and 26 in the maintenance dose (2.4%) were observed in 9 patients. The percentage of reactions/total injection number was 2.2%; all reactions were mild-to-moderate. Fourteen patients reported documented field stings at least two months after VIT onset with only one reported mild systemic reaction. CONCLUSION: We propose a simple "rush" VIT protocol in an outpatient setting as an easy-to-perform alternative option for VIT induction phase.

Treatment of nail psoriasis with a two-compound formulation of calcipotriol plus betamethasone dipropionate ointment.

BACKGROUND: Treatment of nail psoriasis remains a challenge. OBJECTIVE: To evaluate the efficacy of a two-compound product of calcipotriol plus betamethasone dipropionate ointment on nail psoriasis in an open-label study. METHODS: Twenty-five psoriatic patients with nail involvement and mild cutaneous psoriasis were instructed to apply a calcipotriol-betamethasone valerate ointment formulation once daily for 12 weeks on affected nails. Outcome measures were assessed at baseline and at weeks 4, 8 and 12 using the nail psoriasis severity index (NAPSI). RESULTS: Twenty-two patients having 114 nails involved at baseline with a mean NAPSI of 5.8 +/- 1.7 were followed up for 12 weeks. The mean NAPSI at the end of the treatment period was reduced to 1.6 +/- 0.6 presenting a 72% improvement. Significant improvement was observed for hyperkeratosis and onycholysis (reduction of mean hyperkeratosis NAPSI from 2.2 +/- 0.5 to 0.5 +/- 0.1 and mean onycholysis NAPSI from 2.0 +/- 0.6 to 0.4 +/- 0.2), moderate improvement for oil drops (reduction of mean oil drop NAPSI from 1.2 +/- 0.4 to 0.8 +/- 0.3) and slight improvement for pitting (reduction of mean pitting NAPSI from 0.8 +/- 0.2 to 0.6 +/- 0.2). CONCLUSIONS: The calcipotriol plus betamethasone dipropionate two-compound ointment, applied once daily for 12 weeks, was shown to improve nail psoriasis.

Serum levels of transforming growth factor-beta1 in patients with mild psoriasis vulgaris and effect of treatment with biological drugs.

BACKGROUND: Psoriasis is an immune cell-mediated disease in which cytokines play an important role. Studies have been performed to explore the relationship between the disease and cytokine blood levels with a view to finding a biomarker for monitoring disease severity/activity and treatment efficacy. AIM: To investigate the levels of transforming growth factor-beta1 (TGF-beta1) in patients with mild psoriasis vulgaris (PV) and the possible use of this cytokine in monitoring treatment with biological drugs. METHODS: Serum levels of TGF-beta1 were estimated in 33 untreated patients (PI group), in 7 of these patients (PII group) before and after 3 months of treatment with one of two biological drugs (etanercept and efalizumab) and in 19 healthy volunteers (control group). RESULTS: Significantly (P < 0.0001) higher serum levels of TGF-beta1 were found in the PI group [Psoriasis Area and Severity Index (PASI) 9-10] compared with the 19 healthy volunteers. In the PII group, after the administration of one of the biological drugs, a 50% reduction in PASI and a significant (P = 0.032) decrease in TGF-beta1 was noted. CONCLUSIONS: Raised TGF-beta1 levels in patients with mild PV decreased in tandem with a decrease in PASI after biological drug treatment. Hence, TGF-beta1 levels seem to be sensitive to changes in disease severity.

Pathogenesis of subacute cutaneous lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) is a photosensitive form of lupus-specific skin lesion that is strongly associated with the presence of anti-Ro/SSA autoantibody. The pathogenesis of SCLE includes genetic, environmental and immunologic factors. Recent studies provide strong evidence for the involvement of innate and cell-mediated immunity, underlying the important role of plasmacytoid dendritic cells, interferon-alpha and antibody-dependent cell cytotoxicity. In addition, a variety of cytokines, chemokines and adhesion molecules have been found to participate in the expansion phase of the autoimmune effector mechanisms. This article summarizes the recent immunological findings and reviews the current mechanisms which are implied in the development of the disease.

Alopecia areata: topical immunotherapy treatment with diphencyprone.

UNLABELLED: BACKGROUND Topical immunotherapy with diphencyprone (DPCP) is considered the most effective treatment of alopecia areata (AA). OBJECTIVE: To assess the efficacy of DPCP in the treatment of extensive or long-lasting AA in Greek patients. METHODS: Sixty-four patients with extensive and/or long-lasting AA were sensitized with 2% diphencyprone. During each weekly subsequent visit, patients were treated with gradually denser concentrations adjusted in order to maintain erythema and itch on the patient's scalp for 48 h. Patients' hair re-growth was evaluated every 3 months for 2 years. RESULTS: Forty-five patients responded among the 54 completing therapy (83.3%). Initial response was observed 3.48 +/- 1.05 months after the initial treatment. Twenty patients among the responders achieved a grade 4 response, 15 patients achieved grade 3, 9 patients achieved grade 2, and 1 patient achieved a grade 1 response. The mean duration of treatment until maximum response was 6.14 +/- 1.48 months. Thirty-one patients (68.9%) had a relapse during follow-up and were treated again. The only adverse event among patients completing therapy was contact dermatitis of the face or neck (9 of 54) that resolved after topical corticosteroid application within 7 days. Statistical analysis did not establish any association among duration of AA, age, gender, atopic diathesis, nail involvement and presence of thyroid antibodies with response to treatment. CONCLUSION: Treatment of Greek patients with AA with diphencyprone presents high response rates similar to those reported by previous studies. The treatment is adequately tolerated by most of the patients, and they are willing to repeat it in cases of relapse.

Immunological study of keratoacanthomas.

Twelve patients with keratoacanthoma were studied to assess the role and importance of immunological factors in tumor regression. Direct immunofluorescence was determined with immunoglobulins, complement (C3), and fibrin to estimate the deposition of these factors in the lesion area. Indirect immunofluorescence was also undertaken using pemphigus and bullous pemphigoid sera against the keratoacanthoma lesion to study the presence or absence of tissue-specific antigens (T.S.A.) in intercellular substance and basement membrane. Finally, the cell-mediated immunity was studied using two in vitro parameters: (a) The estimation of T-lymphocytes through the formation of E-rosettes and (b) the estimation of the leukocyte migration inhibition factor (LIF). Our findings show that specific humoral immune mechanisms are apparently not involved in the spontaneous regression of keratoacanthoma. Cell-mediated immune mechanisms are evidently not responsible for the resolution of the tumor.

Evaluation of the autoimmune response in leprosy.

Immunological responses to a panel of antigens were evaluated in 27 patients with lepromatous and 20 patients with tuberculoid leprosy and compared with 24 pulmonary tuberculosis patients, 25 systemic lupus erythematosus patients and 41 healthy blood donors. Some autoantibody specificities were extensively studied for the first time in mycobacterial infections. Striking immunoserological abnormalities were found in patients with lepromatous leprosy, particularly in those presenting with relapse. Inhibition assays were performed, providing a tool for further analysis of the binding range of specific anti-N.D.O. BSA antibodies and strengthening the suggestion of molecular mimicry reactions between cytoskeletal proteins, host stress proteins and Mycobacterium leprae antigens or stress proteins. A significant serological overlap between lepromatous leprosy and autoimmune diseases is indicated.