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.

Expression of SOCS1 and SOCS3 Genes with Human Cytomegalovirus Infection After Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3038-3038
Author(s):  
Tae Hyang Lee ◽  
Ji Yoon Lee ◽  
Sohye Park ◽  
Jae-Ho Yoon ◽  
Seung Hwan Shin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Myelogenous Leukemia ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Acute Myelogenous ◽  
Cmv Reactivation

Abstract Abstract 3038 Background: After allogeneic hematopoietic stem cell transplantation (HSCT), cytomegalovirus (CMV) infection is highly prevalent in recipients. Although the suppressor of cytokine signaling (SOCS) genes are mainly regarded as pivotal negative feedback regulators for signaling of cytokines, the expression pattern of SOCS genes in CMV infections remains largely unexplored. To understand the molecular mechanism of cytokine cascades associated with CMV infection, we investigated the expression of SOCS genes from various types of hematologic malignancies after allogeneic HSCT. Methods: In the present study, we investigated SOCS1 and SOCS3 gene expressions, in order to examine the feasibility of SOCS genes as a promising therapeutic target as well as a prognostic predictor in CMV infection. A total of 99 recipients with acute myelogenous leukemia (AML; n=64), acute lymphoblastic leukemia (ALL; n=23), myelodysplastic syndrome (MDS; n=12), who received allogeneic HSCT and 55 normal donors were included. Real-time quantitative polymerase chain reaction (RQ-PCR) was used and all sample analyses were performed in triplicate. Results: The expression levels of the SOCS3 gene were clearly decreased in recipients compared to normal donors, including in the Pre-HSCT, Post-HSCT No CMV, and Post-HSCT CMV subgroups (P=0.0007, P=0.0009, and P=0.0014, respectively). Meanwhile, expressions of SOCS1 gene were significantly decreased in the Pre-HSCT, Post-HSCT No CMV, and normal donors, when compared to Post-HSCT CMV subgroup (P=0.026, P=0.0129, and P<0.0001, respectively), suggesting a correlation between expression of SOCS genes and CMV reactivation. In addition, expression of SOCS1 gene was remarkably increased in patients who received allogeneic HSCT with myeloablative conditioning (MAC), compared to reduced-intensity conditioning transplantation (RIST) and normal donors (P=0.0119, P=0.0002, respectively), while, both regimen with MAC and RIST showed a decreasing pattern with statistical significance compared to normal donors (P=0.0037, P=0.0024, respectively). Notably, SOCS1 gene expression in acute lymphoblastic leukemia and myelodysplastic syndrome recipients were higher than acute myelogenous leukemia, when compare to normal donors (P=0.0239). Furthermore, high expression of SOCS1 gene unarguably showed high mortality (P=0.0068). In AML patients, decreased SOCS3 gene was detected (P=0.0007) and overall high expression of SOCS3 gene was displayed high mortality, but there is no statistical significance. Conclusions: We firstly report that the SOCS genes are differently expressed in human CMV infection after allogeneic HSCT, suggesting a correlation between cytokines by modulation of SOCS genes associated with CMV reactivation. This result provides a new platform for studying CMV immunobiology and these genes may be a potential of diagnostic and therapeutic targets in post-allogeneic HSCT associated with CMV infection. Disclosures: No relevant conflicts of interest to declare.

Oral Valganciclovir As Preemptive Therapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5855-5855 ◽  
Author(s):  
Vildan Ozkocaman ◽  
Fahir Ozkalemkas ◽  
Ridvan Ali ◽  
Yasemin Karacan ◽  
Tuba Ersal ◽  
...  
Keyword(s):  
Stem Cell ◽  
Viral Load ◽  
Myeloid Leukemia ◽  
Preemptive Therapy ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Intravenous Ganciclovir ◽  
Hematopoietic Stem ◽  
Cmv Disease ◽  
Cmv Reactivation

Abstract Introduction: Cytomegalovirus (CMV) infection remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (AlloHSCT). Preemptive therapy with oral VGC or intravenous ganciclovir has replaced universal prophylaxis. We investigated the effect of oral VGC as preemptive therapy on CMV reactivation or infection in AlloHSCT. Patient & Methods: We retrospectively studied 30 consecutive adult recipients of HLA-identical sibling allogeneic peripheral blood stem cell transplant from June 2011 through June 2014 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. Among 30 patients we studied the results of 13 patients with CMV DNA positivity. All 13 recipients and their donors were seropositive for CMV Ig G status. Their diagnosis of pretransplantation were as 8 acute myeloid leukemia (61 %) and 5 acute lymphocytic leukemia (39 %). Median age was 39 years (range 21-54). There were 9 men and 4 women (Table-1). The patients received no prophylaxis against CMV. Blood/serum samples from all patients were routinely monitored for CMV-DNA using PCR twice weekly. We iniciated pre-emptive therapy for CMV as the viral load was above and equal to 500 copies/ml in two consecutive samples. VGC was given twice daily 900 mg for 2 weeks, and maintened at a dose daily 900 mg until viral load is undetectable. Results: The PCR test was persistently negative in 17 patients (57 %) and positive at least once in 13 (43%)patients. All patients with CMV reactivations were on immunsupressive treatment. CMV infection was cleared in most patients within 2 weeks, but for those with stable or increasing CMV levels, the induction period was continued. Twelve patients were treated with oral VGC on an outpatient basis and they all became CMV negative after the first week of treatment. Only one patient received intravenous ganciclovir and he was also CMV negative after the first week of treatment. While no positivity was identified in any of the patients who received VGC on day 21, clinically unimportant low titer CMV positivity was noted in three of these patients. VGC was continued at same dose and no positivity was detected after 2-3 weeks. We were obligated interrupt VGC in only four patients for serious side effects namely neutropenia and thrombocytopenia. We did not observe CMV-related mortality. Conclusions: We concluded that VGC therapy could be safely used at outpatient clinics, with frequent monitorization to prevent severe myelotoxicity. In conclusion, based on our findings, oral VGC is effective and safe in the pre-emptive treatment of CMV disease following allo-HSCT. Therefore, preemptive strategy by oral VGC appears preferable to the prevention of CMV disease in alloHSCT with its advantage of effectiveness and usage in outpatient clinic condition. Table- 1: Management and outcome of the patient characteristics with CMV-reactivation Patients with CMV reactivation/Total number of patient 13/30 Median age, years (range) 39 (21-54) Gender Male Female 9 4 Diagnosis AML ALL 8 5 CMV serologic status Donor+/Recipient + 13 Preperative regimen Bu-Cy CY-TBI Flu/Amsc(FLAMSA) 8 4 1 GVHD propylaxis CSA+MTX CSA+MTX+MM 12 1 GVHD prior to CMV reactivation Acute chronic without GVHD 7 1 5 Prednisolone treatment at the time of starting VCG Yes No 8 5 IST at the time of starting VGC Yes No 13 0 Median duration of CMV reactivation (day) 44 (8-330) Viral load before antivial treament (copies/ml) 1153 (78-12800) Treatment VGC (900 mg, twice daily for induction) GC (5 mg/kg, twice daily for induction) VGC+GC 9 (70 %) 1 (7 %) 3 (23 %) Total treatment duration (day) 24 (10-51) CMV DNA at the end of the treatment Conversion to negative Persistently positive (low titer < 50 copies/ml) 10 (77 %) 3 (23 %) Serious side effects Interruption of therapy due to neutropenia Interruption of therapy due to thrombocytopenia Reactivation 3 (23 %) 1 (7 %) 2 (15 %) Abbreviations: AML: acute myeloid leukemia, ALL: acute lymphoblastic leukemia, CMV: cytomegalovirus,GVHD: graft-versus host disease, CSA: cylosporine, MTX: methotrexate, MMF: mycophenolate mofetil, PDN:prednizolone, IST: Immunosupressive treatment, VGC: valganciclovir, GC: ganciclovir, Bu: Busulfan, Cy: cylophosphamide, TBI: total body irradiation Disclosures No relevant conflicts of interest to declare.

scholarly journals Blinatumomab In pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

2022 ◽  
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Noemi Mergen ◽  
Peter Bader ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Molecular Abnormalities

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific T-cell engager molecule, for treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) were examined in an open-label, single-arm, expanded access study (RIALTO). Children (&gt;28 days, &lt;18 years) with CD19+ R/R B-ALL received up to five cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary endpoint was incidence of adverse events. Secondary endpoints included complete response (CR) and measurable residual disease (MRD) response within the first two cycles, relapse-free survival (RFS), overall survival (OS) and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (1/10/20), 110 patients were enrolled (median age, 8.5 years; 88% ≥5% blasts at baseline). Blinatumomab treatment resulted in a low incidence of grade 3-4 cytokine release syndrome (n=2 [1.8%]) and neurologic events (n=4 [3.6%]). No blinatumomab-related fatal adverse events were reported. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95%CI: 11.0─not estimable) and was significantly greater for MRD responders versus MRD non-responders (not estimable vs 9.3; HR 0.18, 95%CI: 0.08─0.39). One-year OS probability was higher for patients who received alloHSCT versus without alloHSCT post-blinatumomab (87% versus 29%). Median RFS for MRD responders (n=57) was 8.0 months (95%CI:3.4─10.1) versus 2.8 months (95%CI: 0.3─9.2) for MRD non-responders (n=10). Of patients achieving CR after 2 cycles, 73.5% (95%CI: 61.4%-83.5%) proceeded to alloHSCT. These findings support the use of blinatumomab as a safe and efficacious treatment for pediatric R/R B-ALL. (ClinicalTrials.gov identifier NCT02187354)

scholarly journals 1098. Norovirus Infection in Cancer Patients Undergoing Chimeric Antigen Receptor T-cell Immunotherapy (CAR-T)

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S578-S579
Author(s):  
Divya S Kondapi ◽  
Sasirekha Ramani ◽  
Adilene Olvera ◽  
Robert L Atmar ◽  
Mary K Estes ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Nucleic Acid Amplification ◽  
High Dose ◽  
Cell Transplant ◽  
Research Support ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T

Abstract Background CAR-T is used to treat certain refractory hematological malignancies. B-cell aplasia and immunosuppression used to treat CAR-T side effects increase infection risk. Little data are available describing Norovirus (NoV) infections in CAR-T recipients. Methods We reviewed the medical records of 134 patients with NoV diarrhea (identified by nucleic acid amplification test) between 2016-2019. Of these patients, nine received CAR-T prior to developing NoV. Here we describe their demographics, clinical characteristics, treatments, and complications. Results The median age was 49 years (Table 1). Patients’ underlying malignancies included Non-Hodgkin’s Lymphoma (4), Acute Lymphoblastic Leukemia (3), Chronic Lymphocytic Leukemia (1) and metastatic Sarcoma (1). Prior to development of NoV, six patients had undergone hematopoietic stem cell transplant, and 1 had received checkpoint inhibitor therapy. Five patients experienced cytokine release syndrome after CAR-T, and 1 experienced CAR-T-related encephalopathy syndrome (Table 2). Two patients received interleukin-6 antagonist therapy, and one received high dose steroids. Time to diarrhea onset post-CAR-T cell infusion was variable(median 256days, IQR 26-523 days).Six had an absolute lymphocyte count&lt; 1000/mm3 at diarrhea onset. Three had diarrhea for &gt;14 days; median diarrhea duration in the other 6 patients was 4 days. Other GI complaints included abdominal pain (3), nausea (4), and vomiting (3). For NoV treatment, three received oral immunoglobulin, and 8 received Nitazoxanide. Complications included development of concomitant GI-GVHD(5), ileus (2), need for TPN (3), renal failure requiring dialysis (2), ICU stay (3), and death (2). Two patients were co-infected with other enteropathogens such as rotavirus, enteropathogenic and enteroaggregative E.Coli and Clostridioides difficile. Three patients with diarrhea lasting &gt;14 days had serial samples collected over time; NoV shedding lasted 81-546 days. NoV was genotyped in 6 patients(Table 3) and included GII.2(2), GII.4(2), GII.6(1) and GII.12(1). Table 1: Patient characteristics (N=9) Table 2: CAR-T related factors Table 3: NoV Genotypes Conclusion NoV belonging to various genotypes is an important cause of acute and chronic diarrhea in patients receiving CAR-T cell therapy. Disclosures Adilene Olvera, MPH MLS (ASCP), MERK (Grant/Research Support, Scientific Research Study Investigator) Robert L. Atmar, MD, Takeda Vaccines, Inc. (Grant/Research Support) Mary K. Estes, PhD, Takeda Vaccines (Consultant, Grant/Research Support)

scholarly journals Cytomegalovirus Reactivation in Hematopoietic Stem Cell Transplant Recipients in High Endemic Population

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Muhammad Farhan ◽  
Qamar Un Nisa Chaudhry ◽  
Syed Kamran Mahmood ◽  
Tariq Ghafoor ◽  
Raheel Iftikhar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Viral Load ◽  
High Viral Load ◽  
Transplant Recipients ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Endemic Population ◽  
Cmv Reactivation

Background: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). It causes end-organ disease, multi-organ dysfunction syndrome, graft failure, increased susceptibility to infections and GVHD. According to the published western data greatest risk of CMV infection is the seropositivity of the recipient, however, in a high endemic population where seropositivity is up to 100%, risk factors for CMV reactivation are different and are analyzed in this study. Methods: It is a prospective descriptive study performed at Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan from January 2017 to March 2020. Consecutive patients who underwent allogeneic HSCT during this period were enrolled. All patients were prospectively monitored for CMV reactivation by weekly or two weekly CMV DNA quantitative PCR, from engraftment till day 100 post-transplant. CMV infection was diagnosed on detection of more than 200 copies/ml on PCR. Threshold for starting preemptive antiviral therapy was kept at 2000 copies/ml. Patients with past history of CMV infection, those who expired before day 14 post-transplant or those with less than 70% of required CMV tests were not included in the study. Factors associated with CMV reactivation, outcome of antiviral therapy and effect of CMV on post-transplant survival were studied. Results: Out of 319 transplants during this period, 230 patients fulfilled the inclusion criteria. Of these, 197 were HLA matched sibling, 18 were matched family donor and 15 were haploidentical transplants. There were 163 males and 67 females. Median age at transplant was 9.5 years (0.5-53). Eighty-three transplants were done in thalassemia, 55 in aplastic anemia, 14 in Fanconi anemia, 27 in acute leukemias, 8 in CML, 9 in MDS, 12 in HLH and 22 in other hematological disorders. All the patients and donor were CMV IgG seropositive when tested before transplantation. CMV reactivation was seen in 152 out of 230 patients (66.1%). Of 152, 95 patients had CMV viral load more than 2000 copies/ml and required antiviral treatment. Median time to reactivation since transplant was 35 days (13-90). In multivariate analysis using binary regression, risk factors for high viral load CMV reactivation included steroid administration (p=0.009), recipient age less than 10 years (p=0.003) and haploidentical transplant (p=0.048). No statistically significant association was found with the use of ATG, GVHD, underlying disease, ABO blood group or gender mismatch. Survival analysis using cox regression showed significant impact of high viral load CMV reactivation on post-transplant survival. Event-free survival (EFS) with and without CMV reactivation was 70.5 % and 89.7% respectively (p=0.004) and overall survival (OS) was 80.0 % and 97.4 % with and without CMV reactivation respectively (p=0.002). Valganciclovir was given in 89 patients and 6patients were treated with ganciclovir. Mean time to clear viremia was 19.8±9 days. Myelosuppression was seen in 41% of patients treated with valganciclovir. Renal impairment was seen in 25% of patients treated with valganciclovir. One patient had resistant disease. One patient had CMV pneumonia and she recovered. One patient died of suspected CMV pneumonia Conclusion: CMV reactivation was seen in 66.1% of the transplant recipients, this is higher compared to the western world due to high CMV seropositivity is this region. Steroids administration in post-transplant period significantly increase the risk of CMV reactivation. Preemptive therapy with valganciclovir effectively treats CMV reactivation. Viral threshold for treatment should be decided considering the regional endemicity. CMV adversely effects the transplant outcome in terms of EFS and OS. Disclosures No relevant conflicts of interest to declare.

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