Acyclovir Prophylaxis Research Articles

Subcutaneous Low Dose Alemtuzumab: Role As a Salvage Therapy in Immune -Mediated Marrow Failure Conditions

▪Aplastic anemia (AA), pure red cell aplasia (PRCA), pure white cell aplasia (PWCA), idiopathic neutropenia (IN) and T cell large granular lymphocytic leukemia (LGL) are bone marrow failure (BMF) conditions unified by immune-mediated pathogenesis leading to cytopenias. Intravenous alemtuzumab, a CD52 monoclonal antibody approved for the treatment of chronic lymphocytic leukemia (CLL) and used for relapsed AA, has a response rate in AA of 37-58%. However, dosing and route was likely based on those used in CLL regimens and resulted in significant immunosuppressive complications.Here we summarize our experience with sc alemtuzumab given at the maximum dose of total 100 mg as etiologic treatment (either salvage therapy or preferred therapy) to patients with various BMF. We investigated the therapies administered to patients seen at the Cleveland Clinic or at the University of Naples (NCT00895739) between years 2002-2015.Of 484 patients with BMF conditions (Cleveland: AA: 204, LGL: 174, PRCA: 56; Naples: AA: 24, LGL: 2, PRCA: 14), 65 patients with AA (N=22), PRCA (N=22), LGL (N=18) and 3 cases of IN/PWCA were treated sc alemtuzumab, given according 2 distinct schedules: i. initial dose of 3 mg sc followed by 10 mg once or twice weekly for at least 8 consecutive weeks; ii. 4-5 day dose escalation (3-10-30-30-30 mg) regimen. In both schedules, some patients received a much longer course with maintenance treatment or occasional boosts to prevent or treat relapse. Patients received bactrim and acyclovir prophylaxis, IVIG for hypoglobulinemia and underwent CMV monitoring. The median age of patients was 57.5 years (range: 31-84 years). Alemtuzumab was used as salvage therapy in Cleveland (except for 3 AA cases with contraindication to anti-thymocyte globulin or cyclosporine), whereas in Naples untreated patients were allowed per protocol. As a result, patients had a median of 2 lines of therapy (range: 0-6), had either untreated (35%), relapsed (22%) or refractory (43%) BMF condition. Among the 22 AA patients 12 were untreated, or had relapsed (N=4), or refractory disease (N=6), with concomitant PNH clone in 8/22 patients. LGL patients (N=18) treated with alemtuzumab were younger, had a median of 2 prior therapies, 50% were STAT3 mutants, with comparable degree of cytopenias but excess splenomegaly (60% vs. 38%, p=.012) at presentation, compared to the remainder LGL cohort. Amongst these patients, 18% had relapsed LGL while the rest had refractory disease. PRCA cases treated were either idiopathic (N=18, of whom 3 associated with thymoma) or LGL-associated (N=4); this group was very heterogeneous, including 9 untreated patients (in Naples) and a subgroup of heavily pretreated patients (5 with refractory disease) with a median of 5 prior therapies, with mean hemoglobin of 7.5 g/dL. Among the group of PWCA/IN, one case of PWCA was LGL-associated.The treatment was well tolerated in 92% of the patients, except in four patients who did not complete treatment course due to adverse events. The main adverse events include infectious complications with 7/65 developing CMV reactivation, 4/65 HSV reactivation, and more rarely other viral reactivation (VZV and HBV, 1/65 each). Two fatal infections were recorded: 1 fungemia (heavily pretreated with other therapies) and 1 JCV-related PML (in a patients also receiving chemotherapy for refractory thymoma).The overall response rate was 55%; by disease subtype 54% of AA, 44% of LGL, 59% of PRCA and all three cases of PWCA/IN responded. The median time to response in AA was 12 weeks (range: 6-24 weeks), and responses lasted a median of 6 months (range: 2-72 months). In AA, we observed responses in 72% of the cases treated with almetuzumab upfront and 45% of the relapsed/refractory disease. Similarly in PRCA cases, 77% of the alemtuzumab upfront and 46% of the relapsed/refractory disease responded. With a median follow up >4 years, no late treatment-related complication emerged; treatment failures were mostly due to relapses (sometimes refractory to further immunosuppressive treatment), with clonal evolution around 15% (mostly in non-responders).In summary, low-dose sc alemtuzumab is a reasonable alternative option for patients with BMF conditions, especially in relapsed/refractory cases; patients need to be monitored with a heightened vigilance for infectious complications, as well as for possible recurrence of their underlying disease. DisclosuresRisitano:Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Alnylam: Research Funding; Rapharma: Research Funding; Novartis: Research Funding.

Varicella Vaccination of Children With Leukemia Without Interruption of Maintenance Therapy: A Danish Experience.

Varicella-zoster virus (VZV) can be fatal or cause severe complications in children with acute lymphoblastic leukemia (ALL). This analysis set out to investigate the morbidity and mortality of VZV vaccination without interruption of maintenance therapy in children with ALL. Files of 73 seronegative children with ALL were examined for data regarding VZV vaccination and infection, and long-term seroconversion was measured. Criteria before VZV vaccination were (1) seronegative, (2) in complete remission, (3) age ≥ 1.0 year, (4) lymphocyte count ≥ 0.6 × 10/L at time of vaccination and (5) receiving maintenance therapy. Forty-five children were vaccinated. No child died or experienced serious adverse events due to VZV vaccination. Nine children developed late chickenpox despite vaccination. Long-term protection was found in 86% of children not receiving acyclovir and 78% of the entire population. Long-term seroconversion was found in 52% of the children. There were no severe cases of varicella infection. Acyclovir prophylaxis postvaccination was associated with an increased risk of late chickenpox [hazard ratio = 5.40 (1.43, 20.41), P = 0.01]. In contrast, a vaccine-induced rash reduced the risk of late chickenpox [hazard ratio = 0.08 (0.01, 0.66), P = 0.02]. No child had interruption of maintenance therapy at the time of vaccination, but 33% experienced discontinuation of therapy due to vaccine-induced rash. Dexamethasone was associated with an increased risk of vaccine-induced rash [hazard ratio = 2.9 (1.21, 6.90), P = 0.02]. This analysis indicates that VZV vaccination is feasible and justified in seronegative children with ALL, in countries where VZV vaccination is not part of the national vaccination program.

Treatment of Refractory Acute Retinal Necrosis with Intravenous Foscarnet or Cidofovir

ABSTRACTPurpose: To report use of intravenous foscarnet or cidofovir for the treatment of refractory acute retinal necrosis (ARN).Methods: Retrospective chart review.Results: Four immunocompetent men aged 45–90 years presented with ARN from 2008–2014. One patient with two prior episodes of herpes simplex virus (HSV) ARN developed ARN after 6 years of antiviral prophylaxis. His condition worsened on acyclovir followed by intravenous foscarnet but responded to intravenous cidofovir (final VA in involved eye 20/20). Another patient with HSV ARN had received prolonged acyclovir prophylaxis for HSV keratitis; ARN improved after switching from acyclovir to intravenous foscarnet (final VA 20/125). Two patients with varicella zoster virus (VZV) ARN initially responded to acyclovir but developed fellow eye involvement 2–8 weeks later that worsened on acyclovir but responded to intravenous foscarnet (fellow eye final VA 20/20, 20/40).Conclusions: Cases of HSV or VZV ARN that worsen despite intravenous acyclovir treatment may respond to intravenous foscarnet or cidofovir.

Herpes Zoster Is More Frequent in Patients Receiving Higher Cumulative Doses of Arsenic Trioxide and Is Mitigated By Prophylactic Acyclovir

Reactivation of herpes zoster occurs in patients treated with immunosuppressive drugs but is generally not considered an infection associated with either acute myeloid leukemia (AML) or with its intense myelosuppressive treatment. Our institution has been using arsenic trioxide (ATO) since 1997 in all relapsed APL patients and more recently has included it in our front line APL regimens. Here we present a retrospective analysis investigating if ATO treatment is associated with herpes zoster reactivation and whether acyclovir can prevent this in APL patients as well as those with other malignancies on clinical trials.Methods: We evaluated records of patients treated at Memorial Sloan Kettering Cancer Center dating back to 1970, and selected patients with electronic medical records who received ATO treatment either as conventional therapy or as part of a clinical trial (n=213). We also selected records of any patient with a diagnosis of AML over the same period who had not received ATO for use as a control group (n=3366).Results: Among 213 patients who received ATO therapy, 27 (12.7%) were diagnosed with herpes zoster a median of 23 days after the initiation of therapy. This cohort included 76 APL patients, 11 (14.5%) of who were diagnosed with herpes zoster a median of 15 days after the start of therapy (1 days - 5 years). Among the 3366 patients in our AML cohort, 122 (3.6%) were diagnosed with herpes zoster a median of 230 days after the initiation of chemotherapy (2 days - 11 years).In univariate analysis we found a significant association between the likelihood of herpes zoster and ATO treatment (p < 0.01). Patients receiving ATO treatment had a greater than 3 fold odds of herpes zoster compared to non-arsenic treated patients, with a trend toward accelerated development of zoster at cumulative dosages > 1000mg (likelihood ratio test p = 0.28). Acyclovir was strongly protective in both younger and older patients, with an overall relative hazard of 0.07 (likelihood ratio p < 0.01). In a multivariate logistic regression analysis, we found that only arsenic use and older age at diagnosis contributed significantly to the likelihood of herpes zoster diagnosis (p = 0.01), but a diagnosis of APL did not (p=0.89).Conclusion: ATO is now part of the standard of care for treatment of patients with APL. We observed that the incidence of herpes zoster was more common among patients receiving ATO, with a trend toward greater risk at higher cumulative doses. There is evidence to suggest that ATO results in T-cell dysfunction (Morzadec, Bouezzedine, Macoch, Fardel, & Vernhet, 2012; Thomas-Schoemann et al., 2012), which is consistent with the observation that T-cell depleting diseases such as HIV and T-cell directed immunosuppressives are also associated with higher rates of herpes zoster. We therefore suggest including acyclovir prophylaxis in all patients receiving ATO, and continue prophylactic treatment up to 6 months after completion of therapy. DisclosuresDouer:Gilead: Consultancy.

Hematopoietic Stem Cell Transplant in Elderly Patients: Experience from a Tertiary Care Centre in Northern India.

One-fifth of the world’s population resides in India. The burden of hematological diseases both malignant and nonmalignant is huge in the country. According to the registry data the total number of leukemia and lymphoma patients living in India in 2010 was about 100,000 [1]. The estimated size of the elderly population in India is expected to rise from 77 million in 2001 to 140 million by 2021. With the increasing awareness about hematological diseases and the rising economy, many patients are opting for hematopoietic stem cell transplant (HSCT) as a definite treatment for many hematological diseases. The role of HSCT for various hematological diseases in young patients is well established. Older patients have traditionally been considered ineligible for stem cell transplantation and data of HSCT in elderly is scarce, particularly from developing countries. Here we report our experience with stem cell transplantation in the elderly population in India. We reviewed the transplant database at Bone Marrow Transplant (BMT) centre, BLK Superspeciality Hospital, New Delhi. The conditioning regimen for allogeneic HSCT was reduced intensity conditioning (with fludarabine 30 mg/m for 5 days and melphalan 140 mg/m for 1 day). For autologous HSCT for multiple myeloma and lymphoma, melphalan 200 mg/m and BEAM regimens (BCNU 300 mg/m, etoposide 200 mg/m, cytarabine 200 mg/m and melphalan 200 mg/m) respectively were used as conditioning regimens. The transplants were performed in High Efficiency Particulate Air (HEPA) filtered rooms. Peripheral blood stem cell harvest was done after granulocyte-colony stimulating factor (G-CSF) mobilization. Graft versus host disease (GVHD) prophylaxis for allogeneic HSCT included cyclosporine and methotrexate. Patients received standard anti-viral prophylaxis with acyclovir and Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole. Patients were treated with broad spectrum antibiotics at the time of their first neutropenic fever, and with antifungal agents as per institutional policy. The study was approved by the Institutional Review Board. Out of 440 patients who underwent HSCT at BLK Superspeciality hospital from Feburary 2010 to August 2015, 19 (4.32 %) were C60 years of age. Median age was 63 years (range 60–73 years). There were 14 males and 5 females. Seven patients underwent allogeneic HSCT and 12 patients underwent autologous HSCT. All patients had normal liver and kidney functions and normal left ventricular ejection functions prior to HSCT. Six patients had diabetes well controlled with oral hypoglycemic agents. All allogeneic HSCTs were sibling matched peripheral blood stem cell transplantations. The most common indications for allogeneic and autologous HSCT were acute myeloid leukemia (AML) and multiple myeloma (MM) respectively (Table 1). The donors for allogeneic HSCT were females in five cases and males in two cases with a median age of 56 years (range 51–62 years). The median CD34? stem cell dose was 3.7 9 10/kg recipient body weight (range 1.88–8.77 9 10/kg). Neutrophil engraftment occurred at a median of 11 days (range 9–13 days) and platelet engraftment at 15 days (range 11–26 days). None of the patients had cytomegalovirus (CMV) reactivation. One patient developed grade 2 acute gut GVHD and three patients had limited chronic skin GVHD. Twelve patients & Sanjeev Kumar Sharma sksanjeev13@yahoo.com

Polish consensus guidelines on the use of acyclovir in the treatment and prevention of VZV and HSV infections.

A physician has to perform a benefit-risk assessment each time acyclovir is prescribed "off label" for children. A group of Polish infectious disease experts was created to develop evidence-based guidelines on the use of acyclovir in the treatment and prevention of varicella zoster and herpes simplex infections. In primary varicella zoster virus infections, oral acyclovir treatment is recommended in children over 12 years of age and should be considered in younger children who fall into one of the groups at risk of severe varicella. Intravenous acyclovir therapy in varicella is recommended in patients with immune deficiencies, newborns and in complicated cases. When there is a justified need for prevention of varicella, oral acyclovir prophylaxis may be considered if immunoglobulin cannot be administered, and if it is too late for vaccination. Oral acyclovir treatment of herpes zoster may be beneficial to otherwise healthy patients with a rash in places other than the trunk and in patients over 50 years of age. In immunocompetent patients with herpes simplex infections, indications for treatment with oral acyclovir include primary (genital herpes, skin herpes in children with atopic dermatitis, ocular herpes simplex, severe gingivostomatitis, paronychia and pharyngitis) and recurrent infections. Intravenous acyclovir should be administered for herpes infections in neonates, immunocompromised patients and patients who develop complications including neurological.

Varicella-zoster virus-specific cell-mediated immunity and herpes zoster development in multiple myeloma patients receiving bortezomib- or thalidomide-based chemotherapy

BackgroundThe incidence of herpes zoster is substantial during bortezomib treatment in patients with multiple myeloma (MM). ObjectivesThis study aimed to elucidate the effect of chemotherapy with or without bortezomib in MM patients on their herpes zoster incidence and varicella zoster virus (VZV)-specific cell-mediated immunity (CMI). Study designPeripheral blood mononuclear cells were collected at baseline and after 1 month of bortezomib-based or thalidomide-based chemotherapy and then analyzed using VZV-specific interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. The clinical data from these patients were analyzed in relation to the ELISPOT results. ResultsOf 58 patients analyzed, 39 patients received bortezomib and the other 19 patients, thalidomide. Among them, 5 patients developed herpes zoster during chemotherapy; all 5 were being treated with the bortezomib-based regimen and were not receiving prophylactic anti-viral agents. The median onset of herpes zoster was 32 days (range, 15–95 days) from the initiation of chemotherapy. Among patients who received bortezomib therapy, acyclovir prophylaxis significantly reduced the risk for herpes zoster (100-day cumulative incidence, 0% vs. 49.5%; p<0.001). Spot-forming cell (SFC) counts in the IFN-γ ELISPOT assay decreased from baseline after bortezomib (p=0.011) or thalidomide (p=0.096) treatment. Patients with baseline SFCs greater than 20/106 mononuclear cells exhibited significantly higher incidence of herpes zoster (100-day cumulative incidence, 34.8% vs. 0%; p=0.040). ConclusionsBortezomib treatment significantly reduced VZV-specific CMI, and high baseline SFC counts in patients receiving this treatment without acyclovir prophylaxis were associated with a significantly increased risk for herpes zoster.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment of Patients (Pts) with Multiple Myeloma (MM) Who Are Not Candidates for High Dose Chemotherapy

Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in pts who are ineligible for high dose chemotherapy. Outcomes are more attenuated in pts > 75 yrs old. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for pts with MM. Here we present the updated results of this ongoing trial. Methods Pts with newly diagnosed active MM who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Pts had the option to continue treatment up to 8 cycles or 2 cycles beyond confirmed CR. An interim analysis found this combination to be efficacious but relatively toxic. As a result, the treatment schema was amended to the following: bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Pts achieving at least SD continued on to maintenance bortezomib 1.3 mg/m2 IV/SQ every 2 weeks for 2 years. Acyclovir or equivalent viral prophylaxis was originally recommended and became required on the modified schema. Responses were assessed using the IMWG criteria. The overall response rate (ORR) was defined as ≥ PR. Adverse Events (AEs) were assessed using the CTCAE Version 4.0. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results As of 5/31/2013, 43 pts have been enrolled (18 on the original schema, 25 on the modified schema). The median age was 75 (45-89) and 39% of pts were > 75 (48% in the modified schema). Forty two percent of pts were ISS II and 32% were ISS III. Fifteen (35%) pts remain on treatment, all on the modified schema. Treatment-related Grade 3 hematologic AEs were seen in 30% of pts. Only 1 treatment-related Grade 4 hematologic AE of neutropenia was observed. Treatment-related Grade 3 non-hematologic AEs were seen in 21% of pts. The most common non-hematologic Grade 3 AE was neuropathy, seen in 12% of pts (all but 1 on the original schema). There was 1 treatment-related Grade 4 non-hematologic AE of atrial fibrillation and 1 treatment related death (congestive heart failure). Herpes Zoster was seen in 19% of the pts, all from the original treatment schema. A total of 40 pts were evaluable for response. The ORR was 83% (55% ≥VGPR, 28% PR) plus 17% SD and 0 PD. Of the 23 evaluable pts on the modified treatment schema, the ORR was 83% (52% ≥VGPR and 31% PR). For the 15 pts > 75, the ORR was 93% (60% ≥VGPR and 33% PR). At a median FU of 13.1 months, the 1-year PFS is 79% (0.53-0.92) and the 1-year OS is 83% (0.54-0.95). Conclusion The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in this elderly pt population with a large number of pts over the age of 75 years. The modified schema is better tolerated allowing pts to proceed to maintenance treatment which may eventually translate to improved results. Enrollment is ongoing. Disclosures: Off Label Use: Off-label use of Bendamustine in the Treatment of Multiple Myeloma. Chu:Teva: Research Funding; Millennium: Research Funding. Boccia:Teva: Research Funding; Millennium: Research Funding. Flinn:Teva: Research Funding; Millennium: Research Funding.

Acyclovir Prophylaxis Reduces the Incidence of Herpes Zoster Among HIV-Infected Individuals: Results of a Randomized Clinical Trial.

Human immunodeficiency virus (HIV)-infected persons have higher rates of herpes zoster than HIV-uninfected individuals. We assessed whether twice daily treatment with 400 mg of oral acyclovir reduces the incidence of herpes zoster in a randomized, double-blind, placebo-controlled trial among 3408 persons coinfected with HIV and herpes simplex virus type 2. During 5175 person-years of follow-up, 26 cases of herpes zoster occurred among those assigned acyclovir, compared with 69 cases among those assigned placebo (rates, 1.00 and 2.68/100 person-years, respectively), a relative decrease of 62% (hazard ratio, 0.38; 95% confidence interval, .24-.67; P < .001). Daily acyclovir prophylaxis significantly reduced herpes zoster incidence among HIV-infected persons.

Low-dose acyclovir prophylaxis for the prevention of herpes simplex virus and varicella zoster virus diseases after autologous hematopoietic stem cell transplantation.

Limited data are available on prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) disease following autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively reviewed the clinical charts of 105 consecutive patients who underwent their first auto-HCT at our institution between September 2007 and June 2014. Before August 2009, 30 patients received oral acyclovir at 1000mg/day until engraftment, whereas after September 2009, 69 patients received oral acyclovir at 200mg/day. After engraftment, acyclovir was continued at 200mg/day at the discretion of the attending physicians in both groups. The cumulative incidence of HSV disease at 1year after auto-HCT was 7.7 and 4.5% in patients who received oral acyclovir at 1000 and 200mg/day, respectively (P=0.75). Patients were next divided into three groups according to the timing at which acyclovir prophylaxis was stopped after auto-HCT; at engraftment, between engraftment and 1year after auto-HCT, and later than 1year. The cumulative incidence of VZV disease was 25.8, 7.7, and 0.0% at 1year, respectively. This study suggests that low-dose acyclovir prophylaxis may be effective for preventing HSV and VZV disease after auto-HCT. Our findings support the recommendation of acyclovir prophylaxis within the first year after auto-HCT.

Factors Associated with CMV Disease in Pediatric Hematopoietic Stem Cell Transplantation

Cytomegalovirus (CMV) infection remains a significant source of morbidity in pediatric hematopoietic stem cell transplantation (HSCT). Current strategies for mitigating the effect of CMV on outcome include weekly measurement of CMV viral load in the blood through post-transplant day 100 and use of acyclovir prophylaxis in the peritransplant period in patients at risk for CMV infection (patients in which the HSCT donor or recipient had CMV IgG seropositivity indicative of latent infection). Risk factors predicting CMV infection in pediatric HSCT are not well understood, and factors affecting recurrence of CMV viremia following an initial episode have not been reported. We performed a retrospective review of consecutive cases at our institution between 2011 and 2014 where the recipient was at risk for CMV infection. We calculated odds ratios (OR) and 95% confidence intervals (CI) of CMV reactivation as a function of HSCT characteristics. This study was approved by the Institutional Review Board of the Dana-Farber Cancer Institute. Out of a total of 91 at risk patients, 26 (29%) patients had CMV infection (defined as CMV viremia without target organ involvement) occurring at a median of 46 days following HSCT (range: 9-127). One patient died from biopsy-proven CMV pneumonitis. There was a trend towards recipients with underlying malignant conditions having increased risk of CMV infection compared to others (OR=2.3; 95% CI=0.9-6.0; p=0.08). There was a significantly increased risk of CMV infection in recipients of an umbilical cord blood compared to other sources (OR=9.45; 95% CI=1.8-50.6; p=0.009). Patients with acute graft-versus-host disease (aGVHD) had a significantly increased risk of CMV infection (OR=3.6; 95% CI=1.1-12.1; p=0.04). All patients with viremia received a 14-day course of antiviral and immunoglobulin therapy. Patients who failed to clear the virus completely from the blood at the end of 14 days of therapy had no increased risk of CMV recurrence (p=0.2). A total of 6/26 (23%) HSCT recipients experienced CMV recurrence, at a median of 33 days (range 9-74) following initial CMV clearance. In the subset of recipients who experienced a recurrence of CMV infection, there was a trend toward increased treatment-related mortality (TRM; OR=9.5; 95% CI = 0.7-132; p=0.09). However, among all recipients at risk, CMV viremia was not associated with increased TRM (p=0.7). Pediatric patients seropositive for CMV who receive umbilical cord HSCTs have increased risk for CMV viremia in the post-HSCT period. CMV infection is associated with aGVHD. If treated with antivirals, recurrence of CMV can be prevented. Multiple episodes of CMV viremia may be associated with increased TRM. This study broadens understanding of CMV disease in pediatric HSCT, and is the first to analyze factors influencing recurrence of CMV infection.

Infections Are a Major Cause of Prolongation of Hospital Stay in Hematopoietic Stem Cell Transplants in Tropical, Developing Countries: Profile of a Transplant Center in North India

▪Introduction: There are evidence based guidelines for the prophylaxis and management of infections in hematopoietic stem cell transplant recipients. However, the infection profile of transplant centers differs from center to center even in different regions of the same country. The reported incidence of bacterial, fungal and viral infections ranges widely from 13-60%, 4-30% and 2-16% respectively across the world. Here we report the infection profile in our transplant center.Methods: This was a retrospective study done at a tertiary care referral center in India. Data of hematopoietic stem cell transplants from 2004 –2014 was analyzed. All recipients received trimethoprim-sulphamethoxazole, levofloxacin, fluconazole and acyclovir prophylaxis. Voriconazole was used in allogeneic transplants after 2011. Definite bacterial infections were defined as any positive cultures from blood, urine, sputum, pus. Definite infective diarrhea was defined as stool culture or Clostridium difficile toxin positivity. Definite fungal infection required confirmation by culture or histopathology. Probable fungal infection required one each of host factors, clinical features and mycological evidence. Possible fungal infection required any one of the above three factors. Antifungals were started on day 3-5 as per the febrile neutropenia guidelines. CMV was monitored by RQ-PCR weekly till 100 days post transplant. All recipients were nursed in HEPA (high efficiency particulate air) filtered rooms till the resolution of infection or engraftment whichever was later.Results: Data of first 100 (36 allogeneic and 64 autologous) transplants was analyzed. All patients except 3 developed fever requiring antibiotics. There were 68 documented bacterial infections in 47 transplant recipients (47%). Gram negative were the most frequent isolates 49/68 (72.1%) followed by Gram positive organisms 19/68 (27.9%). Polymicrobial infections were seen in 11 patients (16.1%). Infections were significantly more common in allogeneic (26/36) than autologous transplant recipients (34/64) (p=0.005). Diarrhea was seen in 59 patients. Clostridium difficile toxin positivity was seen in 7 cases (11.8%).CMV infection was seen in 9 allogeneic HSCT recipients (25%). All patients had ongoing GVHD at the time of CMV reactivation and were on additional immunosuppression with corticosteroids. The diagnosis of fungal infection was made in 54 patients (54%). It was categorized as probable in 10 and possible in 44. Definite fungal infections could not be documented in any case. Antifungals were used for a median duration of 4.5 days (SD ±6.9).Infection attributed mortality was 9%. The median duration of antimicrobial usage was 13 days (SD±9.2). The median duration of total hospital stay was 38 days (SD±31.7). The median day of neutrophil engraftment was 12 days (SD±3.5). Multiple regression analysis revealed duration of antimicrobial use to be associated with hospital stay (p<0.0001).Conclusions: Antimicrobials were used for up to one third of the total hospital stay of HSCT. Bacterial and fungal infections were the major cause for prolongation of the hospital stay in our center. The incidence of possible fungal infections is higher than centers in other parts of the world and signifies the need for alternative detection methods to confirm the diagnosis. Whether the agent, host or environment factor in tropical and developing countries, contributes to this increased risk of infections needs to be evaluated in a prospective study. DisclosuresNo relevant conflicts of interest to declare.

2-Hour Cryotherapy Effectively Reduces Severe Mucositis Associated with High-Dose Melphalan Followed By Stem Cell Rescue: Results from a Randomized Trial

▪Introduction: Severe mucositis in the autologous transplant setting has been correlated with adverse outcomes; longer febrile neutropenia duration, doubling of infectious risk, 2.7 additional days of total parenteral nutrition, 2.6 additional days of IV narcotics, increased length of stay (LOS), 3.9-fold increase in 100-day mortality, and US$25,405 increase in hospital charges (Sonis, JCO, 2001 19(8)). In a 40 patient randomized trial investigating cryotherapy (6 hours versus none) following high dose melphalan, grade 3/4 mucositis occurred in only 14% of patients using cryotherapy compared to 74% of patients using saline rinses (Lilleby, BMT, 2006 37). Prolonged cryotherapy is a significant hardship for patients and has resulted in nausea, vomiting, headache, toothache, and chills. We performed a randomized study investigating 2 versus 6 hours of cryotherapy in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) with melphalan conditioning.Hypothesis: We hypothesized that a 2-hour cryotherapy regimen would be non-inferior to 6-hours in severity of mucositis, LOS, and incidence of bacteremia.Methods: We conducted a non-inferiority investigation of 146 sequential MM patients undergoing high dose melphalan with autologous stem cell rescue. Patients were consented and randomized to either 2 (n = 73) or 6 hours (n = 73) of cryotherapy via block randomization based on hemoglobin (less or greater than 11 g/dL), fat free mass (30-50, 50-70, >70 kg), or measured 24hr creatinine clearance (<30, 30-60, >60 mL/min). The cryotherapy process consisted of patients’ melting shaved ice inside their mouth for the designated period of time; flavoring with snow cone syrup was permitted. Inpatient nurse practitioners graded mucositis via WHO criteria. Patients received antifungal (fluconazole) and antiviral (acyclovir or valacyclovir) prophylaxis. Subset analyses investigated the incidence of bacteremia in all patients.Results: Median age was 59 years (range 35 - 72) and 60 (range 38 – 71), and the median measured creatinine clearance was 90.6 mL/min (range 0.2 – 168.7) and 85.4 mL/min (range 21.5 – 196.5) for the 2 hour and 6 hour groups respectively.Length of hospitalization (mean of 15 days) did not differ significantly between the 2 cohorts (p = 0.54). Mucositis was graded daily after melphalan infusion. In the 2-hour cohort, 59% of the patients had mucositis (31 patients with grade 1, 10 with grade 2, and 2 patients with grade 3). In the 6-hour cohort, 64% had mucositis (35 patients with grade 1, 9 with grade 2, and 3 patients with grade 3). These results suggest that 2-hour cryotherapy was not inferior to 6-hour therapy in decreasing mucositis grade. In the entire 146 patient group, approximately 30% developed a positive blood culture after transplant, including 25 (34%) and 20 (27%) in the 6-hour and 2-hour groups respectively. The three most common infectious organisms included gram negatives (n = 12 patients), polymicrobial (n = 7), and non-group A streptococcus (n = 7). In the cohort treated with 2-hour cryotherapy, positive blood cultures did not correlate with grade of mucositis (r = 0.05, p = 0.65).Conclusions: In MM patients undergoing ASCT, 2-hour cryotherapy did not increase mucositis compared to 6-hours. The incidence of blood stream infection was not different between groups. In addition, having an infection did not correlate with grade of mucositis.These results suggest that a 2-hour cryotherapy regimen is not inferior to a 6-hour regimen, and may be considered a standard supportive care measure in patients receiving high dose melphalan. DisclosuresHofmeister:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding; ARNO Therapeutics: Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees.

Rates of Infection in Myelofibrosis Patients Treated with Ruxolitinib

Ruxolitinib is the only JAK 1/2 inhibitor approved by the FDA for the treatment of myelofibrosis (MF). It has been established that ruxolitinib helps improve disease-related constitutional symptoms and splenomegaly. However, studies have shown that ruxolitinib affects several cytokines (IL1, IL6, and TNF-α) and other immune processes (dendritic cells function and T-cell response) and has been linked to increased incidence of opportunistic and non-opportunistic infections. Here we report our experience at the Cleveland Clinic. A total of 50 patients (pts) with MF treated with ruxolitinib were included. The median age of the cohort was 68 years (range: 41-89), 28 of them were males and 22 were females. According to the Dynamic International Prognostic Scoring System (DIPSS), 5 pts had high risk, 23 had intermediate-2 risk, 21 had intermediate-1 risk and 1 had low risk disease. Of these pts, 18 developed infections during their treatment course. Of these infections, 12 were CTCAEv4.0 grade 1-2 and 6 were grade 3-4. Median age of the group was 66 years-old ranging between 50 and 83. Males=9 and females =9. The group was risk-stratified with DIPSS into high risk (N=3), intermediate-2 risk (N=7) and intermediate-1 risk (N=8).The infection started several months after initiation of JAK inhibitor treatment ranging between 2 weeks to 22 months (median of 8 months). Of note, 10 pts had episodes of infections prior to starting ruxolitinib (pneumonia N=5, cellulitis N=3, oral herpes N=2, UTI N=2, genital herpes N=1, Clostiridium difficile diarrhea N=1, viral diarrhea N=1, neutropenic fever N=1, spontaneous bacterial peritonitis N=1 and psoas muscle abscess N=1) . None of the patients had an active infection at the time of starting ruxolitinib. The median total dose given to the pts who developed grade1-2 infection was 20 mg daily, and for those who had grade 3-4 infection it was 15 mg daily. A variety of infections have been reported including pneumonia (N=4), cellulitis\\folliculitis (N=4), Clostridium Difficile diarrhea (N=2), URI (N=1), neutropenic fever (N=1), MSSA bacteremia (N=1), herpes zoster activation (N=2), spontaneous bacterial peritonitis (N=1), perineal abscess (N=1) and one pt had a gluteal abscess after a bone marrow biopsy. Most of these infections resolved using oral or topical antibiotics (N=12). However, 6 pts required hospital admissions, and 5 of them required intravenous antibiotics. One of them required admission to the intensive care unit and two others required surgical interventions. Duration of treatment ranged between 1 to 8 weeks (median 2 weeks). Ruxolitinib had to be discontinued due to the severity of the infection in 2 pts, while the others either had a dose reduction or no dose alteration. Two pts required prophylactic antibiotics; one had recurrent SBP despite antimicrobial prophylaxis, while another pt required acyclovir prophylaxis while receiving glucocorticoids with ruxolitinib with no reactivation of Zoster infection. Predisposing factors for infections included a procedure (BMBx N=1), the concurrent use of other immunosuppressive drugs (steroids N=3, other agents N=3) and the prior use of systemic antibiotics in the pts who had C Diff infections (N=2). Only 2 pts had subsequent infections, one had oral herpes and the other had candida esophagitis which required hospitalization and treatment with IV antifungal drugs while on high dose steroids (dexamethasone 4 mg PO twice daily) for immune thrombocytopenia at the time of infection. Though 5 pts had already died at the time of the chart review, none of them died of infectious complications. In summary, infections can occur in patients treated with ruxolitinib but are generally mild. Most infections resolve after an adequate course of oral antimicrobial therapy suggesting that prophylactic antimicrobial agents may not be necessary or cost-effective in the vast majority of MF pts treated with ruxolitinib. DisclosuresNo relevant conflicts of interest to declare.

Incidence and Risk Factors for Cytomegalovirus Disease in a Colombian Cohort of Kidney Transplant Recipients

Incidence and risk factors for cytomegalovirus (CMV) disease in a Colombian cohort of kidney transplant recipients. CMV infection and disease are important causes of morbidity and mortality in kidney transplant recipients, and its prevalence varies with economic, geographic, and ethnic factors. Among 1620 records from a Colombian reference center, CMV immunoglobulin (Ig)G seroprevalence was found to be 90.9% among recipients and 90.2% among donors. In 86% (n = 264) of the cases, CMV disease occurred during the first 6 months after the transplantation, and the most frequent clinical presentation was CMV syndrome, followed by gastrointestinal disease. The following parameters were independent predictors of CMV disease: serological status of D+/R+ (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.03–2.63) and D+/R− (HR, 2.72; 95% CI, 1.49–4.93), age of the recipient (HR, 1.02; 95% CI, 1.01–1.03), and receiving more than 30 mg of prednisolone by the end of the first month after transplantation (HR, 1.59; 95% CI, 1.22–2.07). Acyclovir prophylaxis or other antiviral agents significantly decreased the risk of disease (HR, 0.41; 95% CI, 0.29–0.58 and HR, 0.34; 95% CI, 0.20–0.58, respectively). In conclusion, we found a high prevalence of CMV infection in a cohort of Latin American transplant recipients. In accord with findings from other regions, serological status is the main risk factor, prophylaxis with acyclovir is effective, and induction with alemtuzumab does not increase the risk of CMV disease.

436Five Year Cumulative Incidence of Herpes Zoster (HZ) in Autologous Hematopoietic Cell Transplant (HCT) Recipients who Received Long-Term Acyclovir or Valacyclovir Prophylaxis

436Five Year Cumulative Incidence of Herpes Zoster (HZ) in Autologous Hematopoietic Cell Transplant (HCT) Recipients who Received Long-Term Acyclovir or Valacyclovir Prophylaxis

442Varicella zoster virus infection after allogeneic hematopoietic cell transplantation in Korean children under relatively short-term acyclovir prophylaxis

Duration of acyclovir prophylaxis, mean±SD, weeks 8.9±2.2 10.5±4.4 0.003 Relapse of underlying malignancy after HCT 10 (30.3) 55 (29.9) 0.962 Epstein-Barr virus reactivation 28 (84.8) 141 (76.6) 0.295 Cytomegalovirus reactivation 20 (60.6) 96 (52.2) 0.371 Acute graft-versus-host disease (≥ Grade II) 12 (36.4) 68 (37.0) 0.948 Chronic graft-versus-host disease 9 (27.3) 63 (34.2) 0.434 Overall death* 5 (17.2) 46 (26.0) 0.312

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment Of Patients (Pts) With Multiple Myeloma Who Are Not Candidates For High Dose Chemotherapy

BackgroundDespite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in pts who are ineligible for high dose chemotherapy. Outcomes are more attenuated in pts > 75 yrs old. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for pts with MM. Here we present the updated results of this ongoing trial. MethodsPts with newly diagnosed active MM who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Pts had the option to continue treatment up to 8 cycles or 2 cycles beyond confirmed CR. An interim analysis found this combination to be efficacious but relatively toxic. As a result, the treatment schema was amended to the following: bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Pts achieving at least SD continued on to maintenance bortezomib 1.3 mg/m2 IV/SQ every 2 weeks for 2 years. Acyclovir or equivalent viral prophylaxis was originally recommended and became required on the modified schema. Responses were assessed using the IMWG criteria. The overall response rate (ORR) was defined as ≥ PR. Adverse Events (AEs) were assessed using the CTCAE Version 4.0. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. ResultsAs of 5/31/2013, 43 pts have been enrolled (18 on the original schema, 25 on the modified schema). The median age was 75 (45-89) and 39% of pts were > 75 (48% in the modified schema). Forty two percent of pts were ISS II and 32% were ISS III. Fifteen (35%) pts remain on treatment, all on the modified schema. Treatment-related Grade 3 hematologic AEs were seen in 30% of pts. Only 1 treatment-related Grade 4 hematologic AE of neutropenia was observed. Treatment-related Grade 3 non-hematologic AEs were seen in 21% of pts. The most common non-hematologic Grade 3 AE was neuropathy, seen in 12% of pts (all but 1 on the original schema). There was 1 treatment-related Grade 4 non-hematologic AE of atrial fibrillation and 1 treatment related death (congestive heart failure). Herpes Zoster was seen in 19% of the pts, all from the original treatment schema. A total of 40 pts were evaluable for response. The ORR was 83% (55% ≥VGPR, 28% PR) plus 17% SD and 0 PD. Of the 23 evaluable pts on the modified treatment schema, the ORR was 83% (52% ≥VGPR and 31% PR). For the 15 pts > 75, the ORR was 93% (60% ≥VGPR and 33% PR). At a median FU of 13.1 months, the 1-year PFS is 79% (0.53-0.92) and the 1-year OS is 83% (0.54-0.95). ConclusionThe combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in this elderly pt population with a large number of pts over the age of 75 years. The modified schema is better tolerated allowing pts to proceed to maintenance treatment which may eventually translate to improved results. Enrollment is ongoing. Disclosures:Off Label Use: Off-label use of Bendamustine in the Treatment of Multiple Myeloma. Chu:Teva: Research Funding; Millennium: Research Funding. Boccia:Teva: Research Funding; Millennium: Research Funding. Flinn:Teva: Research Funding; Millennium: Research Funding.

Bortezomib-Induced Hepatitis B Reactivation

Introduction: It has recently been reported that hepatitis B (HBV) reactivation in patients with lymphoma who are hepatitis B surface antigen (HBsAg)-negative during or after cytotoxic therapy occurs after the use of rituximab and stem cell transplantation. However, clinical data on HBV reactivation in multiple myeloma (MM) patients has not been extensively reported. Bortezomib, a selective proteasome inhibitor, has had remarkable activity in relapsed multiple myeloma (MM). Although well-tolerated, reactivation of viral infections may emerge as a problem in this setting (2). We present a case of MM who developed HBV after bortezomib therapy. Case: A 73-year-old Russian female who had history of marginal cell lymphoma was monitored without needing therapy. Three years later, she developed MM requiring vertebral decompression and focal radiation. While on therapy renal failure ensued and she was started on bortezomib and doxorubicin. After five cycles, this was switched to lenalidomide. Prior to therapy, she was seropositive for anti HBs and HBc with negative HBsAg, indicating a prior natural infection. Her aminotransferase level was normal. She was serially monitored for hepatitis serology at dialysis, with seroconversion one month after change in therapy. Tenofovir was started, and patient recovered her immune status within a few months of therapy. Naranjo adverse drug reaction probability score was 5. Discussion: Bortezomib has significant risk of reactivation of infection by the varicella zoster virus, and acyclovir prophylaxis is recommended. A single case report describes reactivation of HBV after 10 cycles of bortezomib. Bortezomib-associated late hepatitis B reactivation appears to be a unique event that requires further confirmation. The contribution of one cycle of lenalidomide to this seroconversion is unknown.

Ganciclovir, Foscarnet, and Cidofovir: Antiviral Drugs Not Just for Cytomegalovirus.

A child who received a second bone marrow transplant 3 weeks ago as part of treatment for relapsed leukemia has developed fever along with low grade mucositis. The child has been on an acyclovir prophylaxis regimen. Viral culture of an oral specimen has grown herpes simplex virus (HSV) type 1. Serum quantitative polymerase chain reaction tests for cytomegalovirus (CMV) show a 2-log increase in viral load after onset of fever compared with 2 weeks prior. The Hematology-Oncology fellow who calls you for a consult expresses that, in addition to the CMV issue, there is concern that the HSV isolate may be resistant to acyclovir.