Quantitative polymerase chain reaction (QPCR) for cytomegalovirus (CMV) is emerging as the preferred screening method for detection of CMV viremia in patients following allogeneic bone marrow and peripheral blood stem cell transplant. However, there are currently no universally accepted QPCR treatment thresholds at which to start preemptive therapy. We report here results of a pre-emptive therapy strategy using ganciclovir (GCV) 5 mg/kg initiated once daily (ODG) delayed till a threshold CMV load of X10 000 copies/ml whole blood in clinically stable patients. Sixty-nine at risk patients underwent allogeneic stem cell transplant. 48/69 (70%) patients had an initial episode of CMV viremia. 5/48 (10%) cleared viremia without requiring treatment. 28/43 (65%) patients requiring treatment initiated treatment with ODG. 17/28 (61%) patients successfully cleared CMV viremia on ODG, 10/28 (36%) patients required dose escalation to twice daily GCV for increasing viral loads. There were two cases of CMV disease (colitis) and no deaths due to CMV disease in patients initiating treatment with ODG. We conclude delaying pre-emptive therapy with ODG until whole blood QPCRX10 000 copies/ ml is a safe and effective strategy for CMV viremia after allogeneic stem cell transplant in clinically stable patients.
CMV infection is a major cause of morbidity and mortality in patients who have undergone ASCT. We previously evaluated the efficacy of ODG (5mg/kg/day) for 21 days as pre-emptive treatment for CMV viremia and found it to be effective and better tolerated than twice daily doses. We now report data evaluating ODG and PT using a quantitative CMV PCR strategy. At our institution, the detection limit of whole blood CMV PCR (WBP) is 200 copies/ml and the lower limit of quantitation 2000 copies/ml. No criteria for a standard treatment threshold currently exist for quantitative CMV PCR in plasma or whole blood. We elected to initiate treatment with ODG using a threshold WBP ≥10,000 copies/ml in clinically stable patients. Dose escalation was permitted for increasing WBP on ODG treatment. From 4/03 to 3/04, 98 patients underwent ASCT (44 related donors and 54 unrelated donors). 69/98 patients were at risk for CMV reactivation (donor/recipient CMV seropositive). Median follow-up was 318 (120–478) days post transplant. 48/69 (69.6%) patients had 1 or more episodes of CMV viremia (WBP >200 copies/ml). In 5/48 (10.4%) patients the WBP remained <10,000 copies/ml. All 5 patients cleared their viremia without treatment. 43/69 (62.3%) patients developed WBP ≥10,000 (11,324–53,000) copies/ml. 15/43 (34.9%) patients initiated treatment with BID ganciclovir (5mg/kg/BID) or foscarnet at the discretion of the treating physician. Most of these patients were acutely ill at the time of initial viremia. Two of these patients developed CMV pneumonitis which contributed to their deaths. 28/43 (65.1%) patients initiated treatment with ODG. Time to onset of viremia was a mean of 37.3 (19–62) days (>200 copies/ml) and 51.7 (27–196) days (≥10,000 copies/ml) post transplant. 10/28 patients increased ganciclovir to 5mg/kg/BID a mean of 12 (4–19) days after initiation of therapy due to increasing WBP (30,200–231,000 copies/ml). One patient developed neutropenia and was changed to foscarnet. In patients for whom WBP were available for the time points indicated, time to clearance of viremia (≤2000 copies/ml) for the 28 patients was 1/21 (5%) week 1, 8/25 (32%) week 2, 14/26 (54%) week 3, 22/27 (82%) week 4 and 26/28 (93%) week 5. Two patients did not clear their viremia at 5 weeks. One developed CMV colitis which was successfully treated. 17/28 patients remained on ODG for the 21 day treatment period. Time to clearance of viremia in this group was 1/10 (10%) week 1, 8/14 (57%) week 2, 12/15 (80%) week 3, 15/16 (94%) week 4, and 17/17 (100%) week 5. Recurrent viremia (WBP ≥10,000 copies/ml) occurred in 12/28 (43%) patients a mean of 109 (54–247) days post transplant. 2/28 (7%) patients developed CMV disease (colitis), 1 during the initial episode of viremia and 1 during a recurrence. Both were successfully treated. There were no deaths due to CMV disease in patients initiating therapy with ODG. Conclusion: Delaying treatment with ODG as initial PT until WBP ≥10,000 copies/ml is a safe and effective treatment strategy for CMV viremia post ASCT. This strategy reduces over treatment of patients and neutropenia.
Background: CMV remains a major cause of morbidity and mortality after aHSCT. The current standard of care for pre-emptive treatment of CMV viremia is IV ganciclovir (GCV). Oral valganciclovir (VGV) has been shown to be effective for the treatment of CMV retinitis in patients with HIV, and offers the advantage of oral administration. This prospective randomized clinical trial was designed to compare VGV to GCV as pre-emptive therapy for CMV viremia in the post-aHSCT population.
Methods: Pts undergoing aHSCT at risk for CMV viremia, determined by donor and/or recipient CMV positivity, were monitored post-aHSCT by weekly quantitative whole-blood PCR. Due to concerns about oral absorption, pts with Grade III/IV gut GVHD were excluded. Positivity was determined by a VL >10,000 copies/mL or >5,000 copies/mL X 2. Pts were randomized to receive either: GCV 5mg/kg BID for 7 days followed by daily GCV 5mg/kg for 7 days or VGV 900mg BID for 7 days followed by 900mg daily for 7 days. At 14 days, PCR was reassessed. Pts with VL <5000 copies/mL completed a 21 day course of daily GCV or VGV. Pts with VL >5000 copies/mL but < initial value completed a 28 course of daily GCV or VGV. Pts with VL > initial value returned to BID GCV or VGV to complete a 28 day course (pts with 21 day level > day 14 level were removed from the study). Primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy.
Results: 37 pts were enrolled and 19 pts received treatment with VGV while 18 pts received treatment with GCV. Patient characteristics were as follows: median age was 53 (range 18–64); 25 males, 12 females; 25 pts had myeloablative conditioning regimens, 12 had non-myeloablative conditioning; 28 pts had unrelated donors, 9 had matched sibling donors; 32 pts received peripheral blood stem-cell products, 5 received bone marrow stem-cell products. These baseline characteristics were equally distributed across the two arms.
Results: VGV and GCV showed equivalent efficacy as pre-emptive therapy (Table below). Toxicities were similar between the two arms: there were 35 grade III/IV events in the VGV arm and 42 grade III/IV events in the GCV arm. There were 20 grade III/IV hematologic toxicities in the VGV arm with 2 grade III episodes of neutropenia and 1 grade III febrile neutropenia. In the GCV arm, there were 23 grade III/IV hematologic toxicities, with 3 grade III episodes of neutropenia and 2 febrile neutropenic events. There were 2 deaths not related to the study medications or CMV. No patients developed CMV disease.
Conclusions: In this trial VGV was equivalent to GCV with regard to clearance of viremia at 28 days. VGV can be considered an alternative pre-emptive therapy for CMV viremia post-aHSCT in patients without evidence of grade III/IV GVHD of the gut.
RESULTS TOTAL VGV GCV p-value Median Time to viremia (days) 38 (16–98) 35 (20–56) 42 (16–98) 0.046 Median Time to initiation of Tx (days) 45 (27–100) 43 (27–80) 49 (29–100) 0.062 Median VL at d0 (copies/mL) 26191 (8964–244895) 44264 (8964–239400) 22948 (10480–244895) 0.35 Median VL at d14 (copies/mL) 5249 (0–497820) 5469 (0–345124) 2562 (0–497820) 0.83 Viremia cleared at day 14 15/37 (40.5%) 7/19 (36.8%) 8/18 (44.4%) 0.74 Viremia cleared at day 21 28/37 (75.7%) 14/19 (73.7%) 14/18 (77.8%) 1 Viremia cleared at day 28 32/37 (86.5%) 17/19 (89.5%) 15/18 (83.3%) 0.66 Recurrent viremia 9 4 5 0.71 Median Time to recurrence (days) 35 (15–54) 39.5 (30–42) 28 (15–54) 0.39
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