Safety and tolerability of cidofovir in high-risk pediatric patients

Abstract: Adenovirus (ADV) infection is a serious complication after hematopoietic stem cell transplantation with significant morbidity and mortality. Cidofovir has emerged as the primary therapy for ADV infection, but its use has been limited by concerns of nephrotoxicity. We report the safety and tolerability of 234 cidofovir infusions in 23 patients at a single institution, and demonstrate evidence of acceptable nephrotoxicity despite concomitant use of other nephrotoxic agents. Three patients suffered adverse events, two related to the hydration regimen associated with cidofovir administration. We conclude that cidofovir is a safe and mostly well tolerated drug in a high-risk pediatric population.     

Neutropenia and renal dysfunction due to intravesical cidofovir for virus‐associated hemorrhagic cystitis after kidney and allogenic hematopoietic stem cell transplantations

We present a patient with virus‐associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo‐HSCT). Six months post‐allo‐HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.     

Low‐dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach

N. Ganguly, L.A. Clough, L.K. DuBois, J.P. Mcguirk, S. Abhyankar, O.S. Aljitawi, N. O'Neal, C.L. Divine, S. Ganguly. Low‐dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach
Transpl Infect Dis 2010: 12: 406–411. All rights reserved Abstract: BK virus (BKV) reactivation occurs in 50% of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) recipients. Standardized antiviral management of BKV infection has not been established. In order to develop a uniform guideline, a treatment algorithm for the management of symptomatic BKV replication was implemented for our allo‐HSCT population. This is a retrospective analysis of patients treated according to the protocol between January 2008 and January 2009. Eighteen patients developed symptomatic BKV replication a median of 43 days after allo‐HSCT. All patients had BK viruria and 12 patients had BK viremia in addition to viruria. Patients with isolated viruria were treated with intravenous (IV) low‐dose cidofovir (0.5–1 mg/kg IV weekly) until symptom resolution. In patients with BK viremia, therapy was continued until virological clearance was achieved in the blood. Four patients also received intravesical instillation of cidofovir per physician discretion. Thirteen of 18 (72%) patients with viruria and 8 of 12 (75%) patients with viremia responded to treatment. Three patients developed transient renal dysfunction. Low‐dose cidofovir is safe and effective in allo‐HSCT recipients. In absence of randomized prospective data, an institutional algorithmic protocol removes variance in practice pattern and derives data that may be used for research and improved patient care.     

Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir

BACKGROUND: Adenovirus (ADV) infection occurs in 5-21% of allogeneic hematopoietic stem cell transplants (HSCT). Symptomatic enteritis and hemorrhagic cystitis may be encountered but are seldom fatal. In contrast, mortality rates of up to 75% are reported for adenoviral pneumonia or hepatitis. Cidofovir is currently being increasingly used for treatment of adenoviral infections after HSCT. The efficacy of cidofovir in patients with invasive adenoviral infection is not established. FINDINGS: We reviewed 687 adult and pediatric patients who received allogeneic HSCT at our institution from 1998 through June 2005. ADV was isolated from 64 (9.3%) patients. Eleven patients received cidofovir for invasive disease occurring at median 39 days (range 3-145) post HSCT. The median age was 40 (range 6-61) years. Seventy-three percent received a T-cell-depleted graft and 18% had grade 3-4 graft-versus-host disease (GVHD) of the gut. Three out of 3 (100%) patients with adenoviral pneumonia died. One patient with hepatitis, cholecysitis, and viremia cleared the infection after 3 months. Two out of 7 (28.6%) patients with hemorrhagic colitis or cystitis died of ADV (1 with extensive GVHD). CONCLUSION: Mortality rates of ADV pneumonitis after allogeneic HSCT remain high in the era of cidofovir. Clinical trials are needed to evaluate management strategies for this life-threatening infection.     

Poor outcome of adenovirus infections in adult hematopoietic stem cell transplant patients with sustained adenovirus viremia

H. Omar, Z. Yun, I. Lewensohn‐Fuchs, L. Pérez‐ Bercoff, C. Örvell, L. Engström, G.‐K. Vuong, P. Ljungman. Poor outcome of adenovirus infections in adult hematopoietic stem cell transplant patients with sustained adenovirus viremia.
Transpl Infect Dis 2010: 12: 465–469. All rights reserved Abstract: The outcome of adenovirus (ADV) infections in adult hematopoietic stem cell transplant (HSCT) patients remains poorly characterized. We studied 14 adults and 3 children, who had undergone HSCT and had developed ADV viremia. Peak ADV DNA levels were significantly higher in patients with ADV diseases than in those without (P=0.03). All children survived the ADV infections. Among the 14 adult HSCT patients, 11 were treated with cidofovir, 2 with ribavirin, and 1 did not receive antiviral treatment. Six of the 13 (46%) treated patients developed ADV diseases and 3 of them (23%) died of ADV infections. Sustained viremia (≥3 positive polymerase chain reaction assays during follow‐up) was detected in all patients who finally died of ADV infections. However, 2 adults having had transient ADV viremia either survived or died of diseases other than ADV infections. Our study indicates that the outcome of adult HSCT patients with sustained ADV viremia may be poor, even for those who have received anti‐ADV treatment.     

Combination therapy for multidrug‐resistant cytomegalovirus disease

Multidrug‐resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV‐seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV‐seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re‐transplantation from a CMV‐seropositive donor supported by adoptive transfer of pp65‐specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches.     

Adenovirus causing fever,upper respiratory infection,and allograft nephritis complicated by persistent asymptomatic viremia

A 20‐year‐old woman, with renal transplant complicated by recurrence of focal segmental glomerulosclerosis and post‐transplant lymphoproliferative disorder, presented nearly 2 years after transplantation with fever, conjunctivitis, and sinus congestion. She was found to have severe adenovirus (ADV)‐induced granulomatous interstitial nephritis, confirmed by immunohistochemical staining for ADV in the renal biopsy, without urinary symptoms, hematuria, or laboratory evidence of a change in allograft function. Fever, upper respiratory tract symptoms, and evidence of adenoviral infection in the allograft resolved with decreased immunosuppression and treatment with cidofovir and intravenous immunoglobulin. Creatinine rose during treatment and remained elevated, possibly related to cidofovir nephrotoxicity. Despite therapy and continued reduction in immunosuppression, asymptomatic low‐level viremia persisted for a year. In renal transplant patients with ADV infection, allograft involvement should be highly suspected even without overt urinary symptoms or laboratory evidence of allograft dysfunction. Demonstration of allograft involvement may prompt alternative management that could limit continued allograft infection. No clear recommendations exist for management of asymptomatic ADV viremia in solid organ transplant patients.     

Brincidofovir treatment of acyclovir‐resistant disseminated varicella zoster virus infection in an immunocompromised host

Brincidofovir (BCV) is a broad‐spectrum antiviral agent active in vitro against double‐stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir‐ and cidofovir‐resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft‐versus‐host disease who was intolerant to foscarnet.     

Clinical potential of DAS181 for treatment of parainfluenza‐3 infections in transplant recipients

Parainfluenza virus (PIV) infections can cause serious respiratory infections and death in immunocompromised patients. No antiviral agents have proven efficacy against PIV, and therapy generally consists of supportive care. DAS181, a novel sialidase fusion protein that temporarily disables airway epithelial PIV receptors by enzymatic removal of sialic acid moieties, has been shown to inhibit infection with PIV strains in vitro and in an animal model. We describe here the clinical course of 2 immunocompromised patients with PIV‐3 infection, one with a history of lung transplantation and the other neutropenic after autologous hematopoietic stem cell transplantation for multiple myeloma. Both patients had substantial clinical improvement in respiratory and systemic symptoms after a 5‐day DAS181 treatment course, although the clinical improvement in the autologous stem cell transplantation patient also paralleled neutrophil engraftment.     

Brincidofovir clearance of acyclovir‐resistant herpes simplex virus‐1 and adenovirus infection after stem cell transplantation

Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV‐1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein–Barr virus disease with relevant meningoencephalitis responded to rituximab.     

Fludarabine,cyclophosphamide, anti‐thymocyteglobulin,and low‐dose total body irradiation conditioning enables 1‐HLA‐locus‐mismatched hematopoietic stem cell transplantation for very severe aplastic anemia without affecting ovarian function

Allogeneic hematopoietic stem cell transplantation for severe aplastic anemia from an alternative donor is associated with higher risks of graft rejection and severe graft‐versus‐host disease. We developed a conditioning regimen consisting of rabbit anti‐thymocyte globulin, fludarabine, cyclophosphamide, and low‐dose total body irradiation. Two adult female patients with transfusion‐dependent very severe aplastic anemia underwent 1‐locus mismatched transplantation using this regimen. Both patients achieved stable engraftment and the clinical course thereafter was uneventful with persistently normal ovarian function. This novel conditioning regimen may be suitable for alternative donor transplantation for severe aplastic anemia, especially in young female patients. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

One‐year low‐dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group

K. Oshima, T. Takahashi, T. Mori, T. Matsuyama, K. Usuki, Y. Asano‐Mori, F. Nakahara, S. Okamoto, M. Kurokawa, Y. Kanda. One‐year low‐dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group
Transpl Infect Dis 2010: 12: 421–427. All rights reserved Abstract: Varicella zoster virus (VZV) disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). We carried out a trial of 1‐year low‐dose valacyclovir (VCV) prophylaxis against VZV disease to evaluate its efficacy and safety. Patients received oral acyclovir (ACV) 1000 mg/day until day 35 after HSCT. Oral VCV 500 mg/day, 3 times a week, was started on day 36 and continued until 1 year after HSCT. The development of VZV disease was monitored until 2 years after HSCT. A total of 40 patients with a median age of 43 years were enrolled. VCV was well tolerated in all but 1 patient who discontinued it on day 224 because of thrombocytopenia of unknown cause. Seven patients developed VZV disease at a median of 479 days (range 145–651) after HSCT, with a cumulative incidence of 18.5%. Two patients developed breakthrough disease during VCV prophylaxis. The other 5 patients developed VZV disease after the discontinuation of VCV, and 3 of these had developed extensive chronic graft‐versus‐host disease. Visceral involvement and serious complications were completely eliminated. All patients responded to the therapeutic dose of VCV or ACV. One‐year low‐dose VCV can be safely and effectively administered for the prevention of VZV disease after allogeneic HSCT.     

Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges

N.A. Kittan, F. Beier, K. Kurz, H.H. Niller, L. Egger, W. Jilg, R. Andreesen, E. Holler, G.C. Hildebrandt. Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges.
Transpl Infect Dis 2011: 13: 524–530. All rights reserved Abstract: We present the case of a 49‐year‐old male patient with Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorder (PTLD) limited to the brain that occurred 6 months after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical symptoms included mental confusion, ataxia, and diplopia. Magnetic resonance imaging (MRI) revealed cerebellar and periventricular lesions consistent with an inflammatory process. Cerebrospinal fluid (CSF) analysis, but not peripheral blood, was positive for EBV‐DNA, but no malignant cells were found. Brain biopsy was not feasible because of low platelet counts. As we considered a diagnosis of either EBV‐associated encephalitis or PTLD, the patient was treated with rituximab combined with antiviral therapy. However, the cerebral lesions progressed and follow‐up CSF testing revealed immunoglobulin H clonality as evidence of a malignant process. Subsequent treatment attempts included 2 donor lymphocyte infusions (DLI). Despite treatment, the patient died from autopsy‐proven PTLD within 8 weeks of the onset of symptoms. This case demonstrates the clinical and diagnostic challenges of primary cerebral PTLD in a patient following allogeneic HSCT.     

Intestinal amoebiasis in a patient with acute graft‐versus‐host disease after allogeneic bone marrow transplantation successfully treated by metronidazole

Amoebiasis has rarely been reported in patients undergoing hematopoietic stem cell transplantation, although it is a world‐wide infection and extremely common. We present a case of intestinal amoebiasis unexpectedly revealed by colonoscopy after allogeneic bone marrow transplantation from a human leukocyte antigen‐mismatched unrelated donor for acute myeloid leukemia arising from chronic myelomonocytic leukemia and successfully treated by metronidazole.     

Acanthamoeba infection in a patient with chronic graft‐versus‐host disease occurring during treatment with voriconazole

Abstract: We report a case of disseminated infection with Acanthamoeba in a patient with graft‐versus‐host disease after hematopoietic stem cell transplant (HSCT) for acute lymphocytic leukemia. The infection involved the brain, skin, and lungs and occurred despite treatment with voriconazole for mold prophylaxis, and did not respond to treatment with multiple other agents reported to have activity against Acanthamoeba. To our knowledge, infection with Acanthamoeba has been reported in 4 other patients after HSCT or bone marrow transplant, and our case is the first to be diagnosed ante‐mortem.     

Late‐onset visceral varicella‐zoster virus infection presented as acute liver failure after allogeneic hematopoietic stem cell transplantation

Although much less common than localized zoster, initial presentation of varicella‐zoster virus (VZV) as visceral infection can occur especially after allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of post‐transplant visceral VZV infection presenting as fatal acute liver failure. It developed 4 years after allogeneic HSCT when a long‐term prophylactic anti‐VZV agent administration was discontinued. VZV should be listed as a causative pathogen of acute liver failure even years after allogeneic HSCT. Indication for, and duration of anti‐VZV prophylaxis should be further investigated.     

Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

Adenovirus is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation and there is no established therapy. Cidofovir has in vitro efficacy against adenovirus. We performed a retrospective analysis of 45 patients treated with cidofovir for adenovirus from 10 centers. In total, 16 patients had definite adenovirus disease, 13 probable disease, and 16 asymptomatic infections. A total of 31 (69%) patients were successfully treated with cidofovir, 10 failed, and four were not evaluable owing to early death from other causes. Cidofovir therapy was successful in 10 patients with adenovirus disease, 10 patients with probable disease, and in 10 patients with asymptomatic infections. The overall survival at 28 days and 6 months after initiation of cidofovir therapy was 76 and 46%, respectively. Of the patients, 18 developed toxicity associated with cidofovir: 14 developed renal toxicity and four other types of toxicities. We conclude that cidofovir may be useful against adenovirus after allogeneic hematopoietic stem cell transplantation but additional studies are needed.     

Cerebral toxoplasmosis in an adolescent post allogeneic hematopoietic stem cell transplantation: successful outcome by antiprotozoal chemotherapy and CD4+ T‐lymphocyte recovery

Toxoplasmosis is a rare opportunistic infection in pediatric allogeneic hematopoietic stem cell transplant (allo‐HSCT) recipients and associated with severe T‐cell deficiency. Here, we report the successful management of cerebral toxoplasmosis in a 15‐year‐old adolescent 4 months post allo‐HSCT for non‐Hodgkin lymphoma through rapid invasive diagnostics, long‐term antiprotozoal chemotherapy, and an hematopoietic stem cell boost for persistently poor graft function. While supportive care and antiprotozoal chemotherapy achieved stabilization, definite improvement only occurred following recovery of CD4⁺ T lymphocytes to >100 cells/μL. At 5 years after the diagnosis of toxoplasmosis, the patient is in continuing remission with normalized clinical and imaging findings.     

No indication of increased infection rates using low‐dose alemtuzumab instead of anti‐thymocyte globulin as graft‐versus‐host disease prophylaxis before allogeneic stem cell transplantation

Background

Alemtuzumab as part of the conditioning protocol is effective in reducing graft‐versus‐host disease (GvHD), but may be associated with increased infection rates, especially when using high doses (ie, 100 mg).

Methods

We performed a retrospective, single‐center, case‐control study analyzing the rates of neutropenic fever, cytomegalovirus (CMV) reactivation, Epstein‐Barr virus (EBV) reactivation, clinical manifest toxoplasmosis, and clinical manifest human herpesvirus‐6 (HHV6) infection using low‐dose alemtuzumab in comparison with anti‐thymocyte globulin (ATG) as GvHD prophylaxis before allogeneic stem cell transplantation. Forty‐four patients transplanted from unrelated donors between 2001 and 2012 were matched by age, diagnosis, and conditioning regimen and treated either with alemtuzumab 10 mg at day ?2 (respectively, 20 mg in case of mismatch transplantation) or ATG. ATG Fresenius (10 mg/kg for 3 days) or Thymoglobulin (2 mg/kg for 3 days) were used.

Results

Rates of CMV reactivation, EBV reactivation, and clinical manifest HHV6 infection or toxoplasmosis did not differ significantly between both groups until 2 years after transplantation. No case of post‐transplant lymphoproliferative disorder was observed. Also, rates of neutropenic fever during inpatient treatment after transplantation did not differ significantly in both groups.

Conclusion

We saw no indication of increased infections rates when using low‐dose alemtuzumab as GvHD prophylaxis before allogeneic stem cell transplantation in this retrospective analysis.     

Effect of ATG‐F on B‐cell reconstitution after hematopoietic stem cell transplantation

Antithymocyte globulin Fresenius (ATG‐F) is used before hematopoietic stem cell transplantation to prevent graft rejection and graft‐versus‐host disease in patients with HLA‐matched unrelated donors or mismatched volunteers. However, little is known about the effect of ATG‐F on the reconstitution of B‐cell subsets. Sixty‐seven patients were longitudinally studied at day 15, day 30, and then monthly after hematopoietic stem cell transplantation. Conditioning regimes included ATG‐F, which was infused at days 3, 2 and 1 at a dosage of 10 mg/kg/d. Twenty‐seven patients received conditioning regimes without ATG. ATG‐treated patients showed a significant delay of CD19+ B cells in the early recovery period. The absolute numbers of circulating CD19+ B cells were significantly lower (P < 0.05) up to 5 months post‐transplantation compared to non‐ATG patients. The recovery of the memory compartment was delayed in both groups and did not reach normal values 1‐year post‐transplantation. ATG‐treated patient showed significantly lower absolute numbers of circulating CD27+ memory B cells in the first‐month after transplantation compared to non‐ATG patients. In conclusion, treatment with ATG in the conditioning regime of patients undergoing allogeneic hematopoietic stem cell transplantation leads to a significant delay of CD19+ B cells. Thus, ATG seems also to negatively influence B‐cell immune reconstitution.