Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis (BKV-HC) Following Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2085-2085
Author(s):  
Graham Tooker ◽  
Ashraf Z. Badros ◽  
Jennifer Nishioka ◽  
David Riedel
Keyword(s):  
Viral Load ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Bk Virus ◽  
Response To Treatment ◽  
Cell Transplant ◽  
Initial Report ◽  
Hematopoietic Stem ◽  
Common Diagnosis

Abstract Background: BKV HC is a well-known complication following allo-SCT. Supportive care with bladder irrigation and blood transfusions were the only available treatment. Since our initial report (Bridges B et al. Am J Hematol 2006;81:535), several studies confirmed that intravesicular cidofovir is a potential effective treatment for BKV HC. In this study, we report a large series of consecutive patients who developed BKV HC following allo SCT and received intravesicular cidofovir. Methods: We conducted a retrospective review of allo SCT patients who developed BKV HC and were prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were diagnosed with BKV HC. The median age was 50 years (range=23-73), and 18 (55%) were male. Acute myeloid leukemia (n=12, 35%) was the most common diagnosis followed by non-Hodgkin lymphoma (n=7, 21%) and B cell acute lymphoblastic leukemia (n=4, 12%). Conditioning regimens were myeloablative (n=19, 58%) or reduced-intensity (n=14, 42%); 15 (45%) patients received cyclophosphamide, and 22 (67%) received total body irradiation. The median time to onset of HC symptoms following SCT was 37 days (range: 8-178); 17 (52%) patients had acute graft vs. host disease. HC symptom severity ranged from grade 0-4 (median=2). The median BK urine viral load pre-treatment was 100,000,000 IU/ml. Patients received a median of 2 intravesicular treatments (range=1-7) at a dose of 5 mg/kg. Four patients (12%) were also treated concurrently with intravenous cidofovir. 19 (59%) patients demonstrated complete clinical resolution of symptoms, 9 (28%) demonstrated partial response to treatment, and 4 (13%) had no change in symptoms following treatment. These improvements in clinical status were independent of viral load, though most had reductions in the viral load. The median time to symptom resolution was 17 days (range=7-53; n=28). 82% of patients had no recurrent symptoms of HC. The main side effect of intra-vesicular instillation was increased discomfort and bladder spasms; severe in 3 patients (9%). No patient had impaired renal function directly attributable to intra-vesicular cidofovir. At 12 months after BKV HC diagnosis, 26 (79%) patients were alive. Conclusions: To our knowledge this is the largest study of intravesicular cidofovir for BKV HC reported to date; 77% of patients with BVK HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for adding intravesicular cidofovir as a standard tool for the treatment of BKV HC. Disclosures Badros: Celgene: Consultancy, Research Funding; Karyopharm: Research Funding; GSK: Research Funding.

Prevalence and Patterns of Cytomegalovirus (CMV) Reactivation In Adult Acute Lymphoblastic Leukemia Patients on Chemotherapy: Single Center Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2583-2583
Author(s):  
Seema Gulia ◽  
Manju Sengar ◽  
Uma Dangi ◽  
Hari Menon ◽  
Sanjay Biswas ◽  
...  
Keyword(s):  
Viral Load ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Manifestations ◽  
High Dose ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Laboratory Parameters ◽  
Cmv Reactivation

Abstract Abstract 2583 Background: Management of acute lymphoblastic leukemia (ALL) requires use of immunosuppressive agents like high-dose steroids and antimetabolites for prolonged periods which can predispose these patients for CMV reactivation and disease. As opposed to hematopoietic stem cell transplant there has been a real paucity of literature regarding clinical manifestations and management of CMV reactivation in ALL. In countries like India with a background of high CMV seropositivity (>90%), reactivation is a serious concern in ALL patients while receiving chemotherapy. Timely recognition and treatment can avoid the morbidity and mortality as well as help maintaining dose intensity which is the key to achieve cure in ALL patients. Methods: This retrospective case series included adult ALL patients (>14 years) who were being treated with chemotherapy between July 2009 to July 2011 at a tertiary care centre and detected to have CMV viraemia (Real time quantitative PCR with Roche CMV DNA QuantKit). PCR was done in patients with possibility of CMV infection based on clinical suspicion. Case records were analyzed for demography, chemotherapy details, clinical features, laboratory parameters, viral load, antiviral therapy and response. Results: Among 203 adult ALL patients, 23 (males-18, females-5) were detected to have CMV viremia. Median age was 23 years (range, 16–44 years). Occurrence of CMV reactivation was most common during later part of induction or re-induction phase of therapy which includes high dose of steroids (14/23) followed by maintenance therapy with 6-mercaptopurine and methotrexate (5/23) and high dose cytarabine based treatment (4/23). Presenting features were: fever (19/23), fever alone (2/23) respiratory symptoms (9/23), anorexia (10/23), loose stools (8/23), abdominal pain (7/23) and splenomegaly (1/23). Abnormal laboratory parameters were: leukopenia or thrombocytopenia (14/23), deranged liver function tests (12/23). CT thorax was abnormal in 3 patients. Bacterial and fungal co-infection was seen in 5/23 patients. Median CMV viral load was 3.0 ×103 copy numbers (range, 708–1.38×106). Eighteen of these patients were treated with intravenous gancyclovir for a period of 14 days. In remaining 5 patients abnormal clinical and lab parameters improved either with antibiotic therapy or spontaneously. Median time to fever defervescence was 4 days (range, 2–5 days). Blood counts recovered after median period of 5 days (range 3–9 days). Gancyclovir related neutropenia and transaminitis developed in 1 patient. CMV titre became undetectable after a period of 2–4 weeks. Conclusion: Awareness of diverse clinical manifestations of CMV infection and high index of suspicion is important for timely diagnosis. Early diagnosis and treatment with gancyclovir reduces the morbidity, empirical use of other antimicrobials and avoids delays in administration of chemotherapy. Disclosures: No relevant conflicts of interest to declare.

A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia (SWOG 1312)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1634-1634 ◽  
Author(s):  
Anjali S. Advani ◽  
Anna Moseley ◽  
Michaela Liedtke ◽  
Margaret O'Donnell ◽  
Megan Othus ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Grade 3 ◽  
Mixed Phenotype

Abstract The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (INO) has demonstrated promising results in both phase 2 and 3 trials (Kantarjian et al. Lancet Oncology 2012; 13(4): 403-11). Pre-clinical studies have demonstrated superior anti-tumor activity when INO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). In this study, SWOG 1312, we assess the safety of INO in combination with CVP and determine the maximum tolerated dose (MTD) of INO in this regimen for patients with relapsed or refractory (R/R) CD22+ acute leukemia (B-ALL, mixed phenotype, and Burkitts). Here, we present our toxicity results. Methods: Pts were treated at limited SWOG institutions from Apr 2014 to present. INO was supplied by Pfizer and an IND was approved by the FDA. The protocol was reviewed and approved by each institutional review board. Eligibility criteria included: age > 18 years (yrs), > 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received treatment with C (750 mg/m2) intravenous (IV) Day 1, V (1.4 mg/m2) (max 2 mg) IV Day 1, P (100 mg) orally Days 1-5 and IO (dose escalated as in Table 1) IV Days 1, 8, and 15. Each cycle was 28 days, and a maximum of 6 cycles could be administered. Dose escalation was performed using a standard 3x3 design; with the plan to treat 12 pts once the MTD was defined. Dose limiting toxicities (DLTs) were considered: (1) > Grade 4 non-hematologic toxicities with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count (ANC) < 500/ uL or platelet count < 25,000/uL] in a bone marrow with < 5% blasts and no evidence of leukemia that lasts > 35 days beyond the most recent dose of IO; (3) any grade 3 non-hematologic toxicity (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to Grade 2 or better by 7 days beyond the most recent dose of IO; (4) any > Grade 3 elevation in SGOT/ SGPT or bilirubin lasting ≥ 7 days; (5) any IO-related toxicity resulting in permanent discontinuation of IO. Results: As of 7/14/2016, 24 pts have been enrolled: 2 pts were ineligible and 3 pts are currently receiving treatment and are not evaluable for toxicity. Of the 19 evaluable pts, the median age was 49 yrs (range 21-75), 10 (53%) were male, and the median WBC at registration was 9.4 K/uL (range 0.9-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 774 days. Five pts were in 1st relapse, 8 in 2nd relapse, 3 in 3rd relapse, 1 in 4th relapse, and 2 pts were primary refractory. Five pts had received prior allogeneic hematopoietic stem cell transplant (AHSCT); 7 pts had poor risk cytogenetics (Ph+, -7, +8, complex, or hypodiploid). One death occurred during treatment and was attributed to pneumonia. Grade 3-4 hematologic toxicity related to treatment was common: neutropenia (11 pts), thrombocytopenia (7 pts), and anemia (6 pts). Grade 3-4 non-hematologic toxicities were almost exclusively febrile neutropenia. One DLT occurred at Dose Level 3: prolonged myelosuppression. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment, and 1 pt experienced Grade 3 alkaline phosphatase at Dose Level 1. Three pts proceeded to AHSCT after study treatment; 1 pt developed VOD post AHSCT however, this fully resolved. Currently, 3 pts have been enrolled to Dose Level 4. Conclusion: The combination of CVP/IO is well tolerated and only 1 significant hepatic event (which subsequently resolved) was observed despite a heavily pre-treated group of patients. Further toxicity results and dose escalation will be presented at the meeting. Response data will also be presented if enrollment is complete. Disclosures Advani: Pfizer: Consultancy, Research Funding. Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Erba:Pfizer: Consultancy; Juno: Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Agios: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy; Celator: Research Funding; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Ariad: Consultancy; Astellas: Research Funding; Astellas: Research Funding; Celator: Research Funding; Agios: Research Funding; Agios: Research Funding; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy.

scholarly journals Retrospective Evaluation of the Use of Romiplostim after Hematopoietic Stem Cell Transplantation0

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5660-5660
Author(s):  
Elisabetta Xue ◽  
Tatiana Lawrence ◽  
Terry B. Gernsheimer ◽  
Filippo Milano
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Side Effects ◽  
Median Time ◽  
Research Funding ◽  
Receptor Agonist ◽  
Transfusion Requirement ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Background Prolonged thrombocytopenia following hematopoietic stem cell transplant (HSCT) is a common complication associated with risks of major bleeding and high platelet transfusion requirements. Although not approved in the setting of post-HSCT thrombocytopenia, few case series have investigated the use of thrombopoietin (TPO)-receptor agonist romiplostim for patients receiving HSCT. Herein, we reviewed its use in the setting of HSCT at our Institution. Methods From January 2006 to December 2017, 4642 patients received a first HSCT. Of these patients, 2152 (46%) received an autologous HSCT (auto-HSCT) while 2490 (54%) received an allogeneic HSCT (allo-HSCT). Among the patients in the allo-HSCT group, 752 (30%) received a matched related HSCT, 1125 (45%) a matched unrelated HSCT, 278 (11%) a mismatch unrelated HSCT and 335 (13%) a cord blood HSCT. A reduced intensity conditioning regimen was used in 629 (25%) patients receiving an allogeneic HSCT. An adequate clinical response was considered as a reduction of transfusion requirement and a platelet count PLT ≥ 50*103 /µL. This research was approved by the Institutional Review Board (IRB). Results Seven patients (adults n=5, children n=2) received romiplostim for thrombocytopenia. Patients' characteristics are reported in Table 1. All but one (who had CLL-related ITP) received the drug while in remission for the underlying hematologic disease. Romiplostim was used in 6 patients after an allo-HSCT and in 1 after an auto-HCT. Among the allo-HSCT recipients, all 6 reached neutrophil engraftment at a median time of 19 days (range 14-28 days). Romiplostim was administered for ITP (n=2) and poor graft function (PGF, n=4), at a median time of 7.5 months (range 2 - 34 months), with a median of 16 administrations (range 3-18) per patient. All patients received romiplostim weekly, with a median initial and maximum dose of 1 µg/kg (range 1-3 µg/kg) and 9.5 µg/kg (range 3-10 µg/kg), respectively. For the 2 ITP cases, romiplostim was given as third line of therapy, after a lack of response to both high dose steroids and intravenous immunoglobulin. One patient responded to the treatment, achieving a platelet count ≥ 50*103/µL after 2 months, while the other patient did not show any improvement and the drug was discontinued after 3 months. All the 4 PGF cases were thought to be secondary to medications, with one patient also having acute graft versus host disease (GvHD) as possible cause. Romiplostim was given as first line of treatment in all the cases; median platelet counts at the time of starting the treatment was 21*103/µL (range 13-42*103/µL). One patient did not show any response after 4 months of treatment and was subsequently switched to another TPO receptor agonist. Three patients showed a clinical benefit: one patient achieved a stable platelet count ≥50*103/µL after one month, another patient had a partial response achieving transfusion-independence after 3.5 months, but with PLT counts remaining below 50*103/µL; the third patient had a transient increase in platelet counts with decreased transfusion requirement, but the response was lost after two weeks. Overall romiplostim was well tolerated, with no major side effects related to its administration. In two cases mild increase in reticulin stain (grading 0-1) was observed. The auto-HSCT patient receiving romiplostim had Hodgkin's Lymphoma and was diagnosed with recurrent ITP 7.5 years after HSCT, while in complete remission for the underlying disease; he received romiplostim as part of the ITP treatment, and responded to a combination of romiplostim and mycophenolate mofetil without reporting adverse events. Conclusion In our analysis, the use of romiplostim was limited to very few cases of HSCT. The retrospective nature of this study along with a very small and heterogeneous cohort does not allow us to draw any efficacy conclusions. However, our data suggest that romiplostim could be considered a safe option to treat prolonged thrombocytopenia after HSCT. Prospective, randomized clinical trials using TPO-receptor agonists for thrombocytopenia in HSCT are needed to determine efficacy and potential side effects. Disclosures Lawrence: Amgen Inc.: Employment, Equity Ownership. Gernsheimer:Dova pharmaceuticals: Consultancy; Novartis: Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy; Shionogi: Consultancy; Cellphire: Consultancy; Fuji film: Consultancy; Bioverativ: Consultancy. Milano:Amgen: Research Funding; ExCellThera: Research Funding. OffLabel Disclosure: We investigated the use of Romiplostim for thrombocytopenia after hematopoietic cell transplant.

Safety and Clinical Efficacy Of Rapidly-Generated Virus-Specific T Cells With Activity Against Adv, EBV, CMV, HHV6 and BK Virus Administered After Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 148-148 ◽  
Author(s):  
Anastasia Papadopoulou ◽  
Usha L Katari ◽  
Ulrike Gerdemann ◽  
Caridad Martinez ◽  
Kathryn Leung ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
De Novo ◽  
Bk Virus ◽  
Morbidity And Mortality ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Bladder Pain ◽  
Allogeneic Hsct ◽  
Viral Antigens

Abstract Viral infections remain a major cause of morbidity and mortality after allogeneic HSCT. We and others have demonstrated that the adoptive transfer of virus-specific T cells (VSTs) specific for EBV, CMV and Adv antigens can treat infections that are impervious to conventional therapies, but broader implementation and extension to additional problematic viruses has been limited by competition between viral antigens and time-consuming/laborious manufacturing. We therefore developed a simplified 10-day system for generating a single preparation of VSTs with activity against 12 antigens from 5 viruses (EBV, CMV, Adv, BK, HHV6) that commonly cause post-transplant morbidity and mortality. We report our initial clinical results using these pentavalent pVSTs. With NHLBI-PACT support, we prepared 35 clinical-grade pVSTs from PBMCs (3x107 cells/sample) that we exposed to overlapping peptide libraries spanning immunogenic Adv (Hexon, Penton), CMV (pp65, IE1), EBV (LMP2, EBNA1, BZLF1), BK (Large T, VP1) and HHV-6 (U11, U14, U90) antigens. Exposure was followed by a 9-11 day expansion phase in a G-Rex device in the presence of IL4+7, producing a mean of 374x106 T cells (range 99-713x106). These lines were polyclonal, comprising both CD4+ (57±5%) and CD8+ (35±5%) cells and retained expression of the memory markers CD45RO+CD62L+ (58±8%). Their specificity was dependent on the prior viral exposure of the cell donor; 32/35 lines had activity against Adv (Hexon: 446±153; Penton:317±108 SFC/2x105), 20/35 against CMV (IE1: 337±141; pp65 1059±479), 26/35 against EBV (LMP2: 175±87; EBNA1: 116±44; BZLF1: 129±88), 18/35 against BK (Large T: 130±67; VP1: 231±104) and 21/35 against HHV-6 (U90: 66±50; U11: 36±18; U14: 82±21). None of the lines reacted against recipient PHA blasts (mean Cr51release of 1% at a 20:1 E:T ratio). We have administered pVSTs to 10 allogeneic HSCT recipients in a dose escalation study; 4 on DL1 (5x106/m2), 4 on DL2 (1x107/m2) and 2 on DL3 (2x107/m2). There were no immediate infusional toxicities, and no de novo acute GvHD, demonstrating the in vivo safety of these pVSTs even after a single exposure to viral antigens in vitro. Three patients received the cells as viral prophylaxis (days 38-43 post-HSCT) and all remain well and virus-infection free at up to 3 months post-treatment. The other 7 patients received the cells as treatment for one or more active infections between days 59-139 post-HSCT. Based on viral load measurements by day 42 post-infusion, the pVSTs were successful in controlling active CMV (1 complete (CR) and 1 partial response (PR)), EBV (2 CRs, including a case of frank PTLD); Adv (1 CR); HHV6 (1 CR); and BK (3 CR, 1 PR, 1NR) infections. Of note, 3 of our BK virus responders had tissue disease with severe hemorrhagic cystitis and all had marked improvement or disappearance of hematuria following infusion. One subsequently had an episode of transient but severe bladder pain in association with inflammation seen on cytoscopy coincident with a 6 log fall in urine BK viral load. Our only non-responder was a patient with BK infection whose line lacked activity for this virus, likely reflecting the serostatus of the donor. In addition, 3 patients subsequently reactivated other viruses than those for which they were initially treated, but all cleared these infections by week 12, without requiring additional cell infusions (CMV: 1CR; EBV: 1CR; BK: 1CR; HHV6: 1CR). Finally, 1 patient received pVSTs under a single patient protocol as an emergency treatment for widespread and bulky rituximab-resistant EBV-PTLD. Post pVST there was an immediate decline in her EBV viral load with complete and sustained resolution of PTLD, coincident with an increase in circulating EBV-specific T cells. However, the profound anti-tumor activity mediated by the rapidly-expanding EBV-directed T cells also produced a transient systemic inflammatory response syndrome, which was controlled with steroids and anti-TNFR antibody, with no long term adverse effects. Thus, infusion of pVSTs as prophylaxis or treatment has been safe and is associated with the appearance of virus-reactive T cells in peripheral blood that have been able to control infection with all 5 targeted viruses. We are currently exploring the extension of this platform to include additional clinically relevant viruses and are planning to assess the activity of these cells in the 3rd party setting for broader implementation. Disclosures: Off Label Use: Virus-specific CTLs manufactured under an investigator-initiated IND. Vera:Wilson Wolf Corporation: Consultancy, Research Funding.

Intravesicular Cidofovir in the Treatment of BK Virus–Associated Hemorrhagic Cystitis Following Hematopoietic Stem Cell Transplantation

2019 ◽  
Vol 54 (6) ◽  
pp. 547-553 ◽  
Author(s):  
Graham M. Tooker ◽  
Kristen A. Stafford ◽  
Jennifer Nishioka ◽  
Ashraf Z. Badros ◽  
David J. Riedel
Keyword(s):  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Hemorrhagic Cystitis ◽  
Bk Virus ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Bladder Irrigation

Background: BK virus hemorrhagic cystitis (BKV-HC) is a common complication following hematopoietic stem cell transplant (HSCT); optimal management remains uncertain. Supportive care (bladder irrigation and blood transfusions) and intravenous and intravesicular cidofovir have all been used with varying success. Objective: The purpose of this study was to determine the safety and effectiveness of intravesicular cidofovir for BKV-HC following HSCT. Methods: A retrospective analysis of all HSCT patients with BKV-HC prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were treated for BKV-HC. The median age was 50 years (range 23-73), and 18 (55%) were male. The median HC symptom severity was 2, with a median BK urine viral load pretreatment of 100,000,000 IU/mL. Patients received a median of 2 intravesicular treatments (range 1-7) at a dosage of 5 mg/kg per instillation. In all, 19 (59%) patients demonstrated complete clinical resolution of symptoms; 9 (28%) had a partial response; and 4 (13%) had no change in symptoms. Patients with a high pretreatment BK viral load (>100 million) and high HC grade (2-4) had a lower frequency of complete remission. The main side effect of intravesicular instillation was severe bladder spasms in 4 patients (12%). Conclusion and Relevance: This is the largest study of intravesicular cidofovir treatment of BKV HC reported to date; 88% of patients with BVK-HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for this treatment for BKV-HC.

AMC-053: Pilot Study of an Oncolytic Viral Strategy Using Bortezomib with ICE +/- Rituximab for Relapsed/Refractory HIV+ Lymphomas

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 786-786 ◽  
Author(s):  
Erin Gourley Reid ◽  
David Looney ◽  
Frank Maldarelli ◽  
Ariela Noy ◽  
David H. Henry ◽  
...  
Keyword(s):  
Viral Load ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Proteasome Inhibition ◽  
Small Sample ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Viral Loads ◽  
Dose Levels ◽  
The Impact

Abstract Introduction: Both HIV+ Hodgkin and non-Hodgkin lymphomas have higher rates of latent infection by the gamma-herpesviruses (GHVs), Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpes virus (KSHV), than corresponding lymphomas in the HIV-seronegative population. Bortezomib, a proteasome inhibitor, induces lytic activation of both EBV and KSHV. Lytic activation of GHVs latently infecting lymphoma cells is hypothesized to beneficial both for direct tumor cell lysis as well as increased cytotoxic immune response due to viral lytic gene products. Furthermore, preclinical studies found proteasome inhibition impairs HIV infectivity via preservation of human anti-retroviral APOBEC3G, suggesting a novel therapeutic strategy to control HIV. Given that therapy of relapsed or refractory HIV-associated lymphoma (R/R-HAL) results in modest rates of remission, we sought to capitalize on the high viral association within HAL using an oncolytic strategy with bortezomib. Objectives: The primary objective of this study was to evaluate safety and overall response rate (ORR) of R/R-HAL to bortezomib combined with ifosfamide, carboplatin, etoposide +/- rituximab (ICE/R). The secondary objectives of this study were to estimate the impact of bortezomib on lytic activation of EBV and KSHV, using peripheral blood mononuclear cell (PBMC) viral loads, and on HIV using single copy plasma viral loads; to report overall survival at 1 year (1yr-OS); and to correlate EBV and KSHV viral load changes with lymphoma response. Methods: A 3+3 dose escalation design with a 7-day lead-in period of bortezomib alone prior to bortezomib + ICE/R allowed for assessment of early effects of bortezomib on viral loads. Bortezomib was given intravenously on day 1 and 8 of each cycle at one of 4 dose levels: 0.7, 1, 1.3 or 1.5 mg/m2. Standard dose ICE +/- R began day 8 of cycle 1 (28-day cycle); ICE +/- R began day 1 of all subsequent cycles (21-day cycle). Rituximab was included in the regimen only for CD20+ lymphoma. Binomial proportions were used to estimate ORR. The product-limit (Kaplan-Meier) method was used to estimate 1yr-OS. The Wilcoxon signed rank test was used to evaluate changes in viral loads. Results: Twenty-three subjects were enrolled from 7 sites within the AIDS Malignancy Consortium (AMC). More than 90% of enrolled subjects were men and half were minorities; at baseline, 20/23 were on antiretroviral therapy, median CD4 count was 315/µL and median HIV viral load was undetectable. Mean age was 50 years. Over half of subjects had stage IV HAL; the majority had diffuse large B-cell lymphoma (DLBCL) (n=15), 2 had primary effusion (PEL), 3 had plasmablastic and 2 had Hodgkin lymphoma. Figure 1 summarizes grade 3-4 toxicities of the 22 subjects evaluable for adverse events during the dose-limiting toxicity period (cycles 1+2). The maximum tolerated dose was not reached at the highest dose cohort studied (bortezomib 1.5mg/m2). Responses occurred in 14/22 subjects initiating protocol therapy: 5 complete and 9 partial responses (PR). Of the 20 subjects who completed 2 or more cycles, the ORR was 80%. Nine of the responders underwent auto-hematopoietic stem cell transplant after protocol therapy. 1yr-OS was 55%. After bortezomib alone, median values of EBV PBMC viral load measured on day 8 were 2x greater than baseline. However, paired analysis did not confirm significant change in this small sample (n=16 evaluable), and there was no correlation found between change in EBV viral load and response. The 2 subjects with known KSHV+ lymphoma (PEL) each had more than a 1-log increase in day 8 KSHV viral load compared with baseline. Both of these subjects attained a PR from protocol therapy. Conclusions: Addition of bortezomib to ICE/R in R/R HAL is feasible with ORR (80%) and 1yr-OS (55%) comparing very favorably with a prior AMC retrospective report of ICE/R in R/R HAL (n=31, ORR 32%, 1yr-OS 38%, Bayraktar 2012). Evaluation of data collected from individual subjects suggests GHV lytic activation may occur with bortezomib alone. However, the lower bortezomib dose levels used to treat the bulk of study subjects and the limited study sample size limit our power to confirm this conclusion. We plan to further explore the effects of proteasome inhibition on GHVs. Evaluation of the impact of bortezomib on HIV replication is pending and will be presented at the meeting. Disclosures Reid: Millennium: Research Funding. Sparano:Takeda: Research Funding.

Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19027-e19027
Author(s):  
Prasanth Lingamaneni ◽  
Vatsala Katiyar ◽  
Rohit Kumar ◽  
Maha A.T. Elsebaie ◽  
Hashim Mann ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphoblastic Leukemia ◽  
Index Admission ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Hospitalization Costs ◽  
Acute Graft

e19027 Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p<0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p<0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]

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