Gary Schoch

Ganciclovir Prophylaxis To Prevent Cytomegalovirus Disease after Allogeneic Marrow Transplant

Cytomegalovirus (CMV) disease has been an important source of morbidity and mortality during allogeneic marrow transplant [1, 2]. Patients who are CMV seropositive, regardless of the donor status, have an incidence of 69% infection with CMV [2]. Despite recent advances in antiviral therapy, established CMV disease is difficult to treat. Cytomegalovirus interstitial pneumonia remains a disease with a mortality rate of between 30% and 55% [3-5]. Adequate therapy for CMV gastrointestinal disease in patients with marrow transplant has not been well defined [6]. Ganciclovir, an acyclic nucleoside analog, has been shown to have activity against CMV in the treatment of CMV infection in immunocompromised hosts [7-9]. In a recent attempt to prevent CMV disease, ganciclovir was given to marrow transplant recipients excreting CMV after transplant but before CMV disease was diagnosed [10, 11]. Both early treatment studies showed a significant clinical and statistical reduction in CMV pneumonia, gastrointestinal disease, and death after marrow transplantation but failed to identify patients diagnosed with CMV disease without previous positive surveillance cultures. An alternative approach to early treatment strategies is to give ganciclovir at the time of engraftment to all patients who are CMV seropositive. The advantage of this prophylaxis strategy, compared with early treatment strategies, is the inclusion of all patients at risk for developing CMV disease. The concern with ganciclovir prophylaxis is myelosuppression. Therefore, we have performed a randomized placebo-controlled trial of ganciclovir given to CMV-seropositive allogeneic marrow transplant recipients at the time of engraftment and before CMV excretion or disease. Methods Patients Patients who were CMV seropositive before transplant and were to receive an allogeneic marrow transplant for hematologic malignancy requiring total body irradiation or busulfan-cyclophosphamide at the Fred Hutchinson Cancer Research Center were eligible for study entry. Signed informed consent was obtained according to Food and Drug Administration and institutional guidelines. Protocol Design Patients were entered into this double-blind study before transplant and were followed with weekly viral cultures. Patients were assigned randomly to receive ganciclovir or placebo at the time of engraftment, which was defined as an absolute neutrophil count of 0.750 109/L or greater for 2 consecutive days. Ganciclovir was given at a dose of 5 mg/kg body weight, administered intravenously twice daily for 5 days and then once daily until day 100 after transplant. Patients were excluded from the study if they received a T-cell-depleted transplant, were younger than 2 years of age, had a serum creatinine level greater than 220 mol/L, were allergic to acyclovir or ganciclovir, had received a marrow transplant in the previous 6 months, or had documented CMV excretion before randomization. Patients received high-dose acyclovir prophylaxis from the time of conditioning until engraftment [12]. Virus cultures were obtained from urine, blood, and throat on a weekly basis through day 100 or until leaving Seattle, whichever was longer. All patients who began to excrete virus were removed from the study and treated with ganciclovir [11]. Viral infection was defined as recovery of virus from the throat, urine, or blood. Disease caused by CMV was defined as recovery of virus from a visceral site (lung, gastrointestinal tissue) or by bronchoalveolar lavage in patients who had associated signs (pulmonary infiltrate) and symptoms consistent with CMV infection. Marrow toxicity was defined as an absolute neutrophil count of less than 0.750 109/L for 2 consecutive days. Bacterial or fungal infection was defined as the recovery of the organism from a blood culture or other normally sterile site. Laboratory Procedures Virus cultures included both centrifugation culture [13] and conventional culture. Conventional cultures were maintained for 5 weeks. Statistical Design Study end points were the development of CMV infection and marrow toxicity. Development of CMV disease and death were secondary end points. The analysis of infection, disease, toxicity, and mortality was evaluated from start of the study drug to day 100 after transplant. Mortality and disease were analyzed at 180 days after transplant. Comparison of time to specific events was done according to the method of Kaplan-Meier [14] with analysis by log-rank test [15]. Other comparisons were done using the chi-square test, Fisher exact test, Student t-test, or the Wilcoxon test, as appropriate. Fifty patients were entered into the study at which point a scheduled interim analysis was performed. A difference in the incidence of CMV infection between study arms at P = 0.005 was required to stop the study. At the completion of the interim analysis, a statistically significant difference between the study arms for CMV infection was found at the P = 0.005 level, and the study was terminated. Seventy patients had been enrolled in the study by the time the interim analysis had been completed. Sixty-four patients were included in the final analysis. Results From November 1990 to August 1991, 114 consecutive CMV-seropositive patients were eligible for the study. Twenty-one patients were not enrolled, with three refusing study entry and three receiving T-cell-depleted marrow transplants. The other 15 patients were enrolled in protocols that precluded ganciclovir administration or conflicted with the blinded design of our study. Ninety-three patients were entered into the study before transplant. Between transplant and engraftment, 23 patients became ineligible for study before randomization with acute renal failure (eight patients), hematologic relapse (eight patients), refusal (three patients), failure to engraft (two patients), and positive culture for CMV (two patients). Seventy patients were randomized at engraftment and received the study drug. When the interim analysis showed a difference between the ganciclovir and placebo arms, the study was stopped. Five of the 70 patients had not reached an end point when the result of the interim analysis became available. All five of these patients had been enrolled in the study less than 2 weeks and are not included in the final analysis but were treated with ganciclovir during the remainder of their transplant course. None of these five patients developed CMV excretion or disease during the first 100 days after transplant. One additional patient was excreting CMV the day before study entry and received two doses of study drug before culture results became available. This patient was withdrawn from the study and was treated with ganciclovir. This left 64 evaluable patients with 33 receiving ganciclovir and 31 receiving placebo (Table 1). There were no statistical differences between groups except for the day after transplant for study withdrawal and for total days on study. The median day for study withdrawal in the ganciclovir group was 88 days (range, 44 to 114 days after transplant) compared with a median of 59 days (range, 24 to 100 days after transplant) in the placebo group (P = 0.001). This difference was reflected in the total number of days on study with a difference in medians of 25 days between the two groups (P < 0.001). Table 1. Characteristics of Study Groups Effect of Prophylactic Ganciclovir on Cytomegalovirus and Other Herpesvirus Infection Ganciclovir prophylaxis resulted in a marked reduction in CMV infection (Figure 1). Fourteen of 31 (45%) patients on placebo excreted CMV from the start of the study drug to day 100 after transplant compared with 1 of 33 (3%) ganciclovir recipients (P < 0.001). Cytomegalovirus was recovered from urine in eight patients, blood in four patients, and throat cultures in two patients. Four of the 14 patients on placebo who excreted virus at some time after the start of study drug to day 100 after transplant developed CMV gastrointestinal disease. One patient developed CMV interstitial pneumonia 9 days after gastrointestinal disease was diagnosed. Five patients on placebo who developed CMV disease did not have detectable virus excretion before the onset of disease. None of the patients on ganciclovir excreted virus while on the study drug. One ganciclovir recipient who received 4 days of drug had virus isolated from the blood 36 days after stopping drug secondary to neutropenia. Another ganciclovir recipient had virus isolated from the blood on day 104, 40 days after termination from the study for neutropenia. Neither patient developed CMV disease. Figure 1. Cytomegalovirus infection after allogeneic marrow transplant. P Ganciclovir prophylaxis was also effective in suppressing herpes simplex virus excretion. Fourteen of 31 placebo recipients excreted herpes simplex virus while on study, compared with zero of 33 ganciclovir recipients. One placebo recipient had a case of varicella-zoster infection while on study. Effect of Prophylactic Ganciclovir on Cytomegalovirus Disease Ganciclovir prophylaxis was effective in eliminating CMV disease during the first 100 days after marrow transplant. Nine (29%) placebo recipients developed CMV disease from the start of study drug to day 100 after transplant, compared with no cases of disease in the ganciclovir group (P < 0.001). Three patients had CMV interstitial pneumonia, five had gastrointestinal disease, and one patient had pneumonia and gastrointestinal disease (Table 2). The median day to onset of CMV disease was 47 days after transplant (range, 43 to 74 days). Cytomegalovirus interstitial pneumonia was diagnosed earlier than gastrointestinal disease, with medians of 44 (range, 43 to 47 days) and 60 days (range, 45 to 74 days), respectively, consistent with previously published data [1]. Two of the nine patients died of CMV interstitial pneumonia. Table 2. Occurrence of Cytomegalovirus Disease* When analyzed at 180 days after tran

Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia

To determine the incidence of secondary cancers after bone marrow transplantation, we reviewed the records of all patients at our center who received allogeneic, syngeneic, or autologous transplants for leukemia (n = 1926) or aplastic anemia (n = 320). Thirty-five patients were given a diagnosis of secondary cancer between 1.5 months and 13.9 years (median, 1.0 year) after transplantation. Sixteen patients had non-Hodgkins lymphomas, 6 had leukemias, and 13 had solid tumors (including 3 each with glioblastoma, melanoma, and squamous-cell carcinoma). There were 1.2 secondary cancers per 100 exposure-years during the first year after transplantation (95 percent confidence interval, 0.7 to 2.0). The rate declined to 0.4 (95 percent confidence interval, 0.2 to 0.7) after one year. The age-adjusted incidence of secondary cancer was 6.69 times higher than that of primary cancer in the general population. In a multivariate model, the predictors (and relative risks) of any type of secondary cancer were acute graft-versus-host disease treated with either antithymocyte globulin (relative risk, 4.2) or an anti-CD3 monoclonal antibody (13.6) and total-body irradiation (3.9). Two additional factors were associated with secondary non-Hodgkins lymphomas: T-lymphocyte depletion of donor marrow (12.4) and HLA mismatch (3.8). We conclude that recipients of bone marrow transplantation have a low but significant risk of a secondary cancer, particularly non-Hodgkins lymphoma.

Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: the 21-year Seattle experience.

PURPOSE To analyze results of 127 patients undergoing myeloablative therapy followed by marrow transplantation for relapsed or refractory Hodgkins disease. PATIENTS AND METHODS Twenty-three patients had primary refractory disease, 34 were in early first relapse or second complete remission (CR), and 70 had refractory first relapse or disease beyond second CR. Preparative regimens included total-body irradiation (TBI) and chemotherapy (n = 61) or chemotherapy only (n = 66). Sixty-eight patients received autologous marrow, six syngeneic marrow, and 53 allogeneic marrow. RESULTS The 5-year actuarial probabilities of survival, event-free survival (EFS), relapse, and nonrelapse mortality for the entire group were 21%, 18%, 65%, and 49%, respectively. HLA-identical allogeneic marrow recipients had a statistically lower relapse rate compared with recipients of autologous marrow, but survival, EFS, and nonrelapse mortality rates were not significantly different. In the multivariate analysis, higher performance status and absence of bulky disease predicted for improved EFS and lower relapse rates, while fewer prior treatment regimens predicted for improved EFS and lower nonrelapse mortality rates. Additionally, the univariate analysis showed that patients who underwent transplantation with disease refractory to chemotherapy or beyond second CR had a worse outcome compared with those who had less advanced disease. CONCLUSION Outcome with transplantation for patients with Hodgkins disease is improved if transplantation is performed early after relapse when disease burden is less, tumor chemosensitivity is greater, and the patient is likely to have a better performance status. The use of HLA-matched sibling marrow results in a lower relapse rate and, thus, for some individuals, may be preferable to the use of autologous marrow.

Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens.

PURPOSE The impact of a second marrow transplant on long-term disease-free survival (DFS) was evaluated for 77 consecutive patients aged 2 to 51 years who relapsed subsequent to allogeneic marrow transplantation after high-dose chemotherapy and total-body irradiation (TBI). PATIENTS AND METHODS Patients received a second transplant for recurrent chronic myelogenous leukemia (CML) (n = 28), acute myelogenous leukemia (AML) (n = 32), and acute lymphoblastic leukemia (ALL) (n = 15) or lymphoma (n = 2) that used the same marrow donor as the initial transplant. High-dose chemotherapy of busulfan (BU) and cyclophosphamide (CY), or CY, carmustine (BCNU), and etoposide (VP-16), was used as a preparative regimen for the second transplant. Graft-versus-host disease (GVHD) prophylaxis consisted of the following: no prophylaxis (n = 8), T-cell depletion (n = 36), methotrexate (MTX) only (n = 21), cyclosporine (CSP) only (n = 1), MTX and CSP (n = 9), or anti-thymocyte globulin (ATG) and prednisone (n = 2). RESULTS Engraftment occurred in the 74 assessable patients. Severe veno-occlusive disease (VOD) was the most frequent cause of grades 3 and 4 regimen-related toxicity (RRT); it occurred in 20 patients. The probability of death before day 100 from nonleukemic causes was 36%. The probability of relapse after second transplant was 70%, and the DFS rate was 14% (median DFS, 36 months; range, 22 to 87). The DFS rates for ALL, AML, and CML were 8%, 10%, and 25%, respectively. Multivariate analysis showed that the risk of relapse was inversely associated with acute GVHD (relative risk [RR] of relapse = 0.2; P = .0009). No other factor was associated with relapse. DFS was associated with the presence of acute GVHD (RR of treatment failure = 0.5; P = .0085), and a reduction of DFS was associated with severe VOD (RR = 10.6; P = .0001) and those patients older than 10 years (RR = 2.5; P = .0337). CONCLUSION These data show that some patients may benefit from a second marrow transplant for recurrent leukemia after an initial marrow transplant. Younger patients and patients with CML especially should be considered as potential candidates for a second transplant.

Bone Marrow Transplantation for Patients with Myelodysplasia: Pretreatment Variables and Outcome

STUDY OBJECTIVE To determine the efficacy of allogeneic bone marrow transplantation for severe myelodysplasia, and to identify variables predictive of outcome. DESIGN Case series study. SETTING A referral-based bone marrow transplant center. PATIENTS Consecutive series of 59 patients with myelodysplasia or closely related disorders and either life-threatening cytopenia or a progressive increase in marrow blast percentage. INTERVENTION Patients were treated with high-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation from either an HLA-identical (n = 45) or HLA-partially matched (n = 14) donor. MEASUREMENTS AND MAIN RESULTS The product-limit estimate for disease-free survival 3 years after transplant is 45% (95% CI, 32% to 59%). The commonest causes of death after transplant were disease recurrence, interstitial pneumonia, and graft-versus-host disease, accounting for eight deaths each. In a univariate analysis, younger patients, those with shorter disease duration, and those whose disease was characterized by an abnormal cytogenetic karyotype had better survival and disease-free survival than the group as a whole. In a multivariate analysis, younger age and abnormal karyotype were independent predictors of improved disease-free survival and overall survival. Patients who received transplants when they had fewer blasts in their bone marrow had a decreased chance for disease recurrence when compared with patients with excess blasts. CONCLUSIONS Bone marrow transplantation offers a potential cure for many patients with myelodysplasia. Best results can be expected in younger patients who receive transplants relatively early in their disease course.

Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia.

PURPOSE The purpose of this report was to review the Seattle experience in bone marrow transplantation (BMT) for acute myeloid leukemia (AML) during untreated first relapse. PATIENTS AND METHODS Through 1990, 126 patients were transplanted during untreated first relapse of AML. Several preparative regimens were used, two of which involved more than 20 patients. Regimen 1 (29 patients) consisted of cyclophosphamide (CY) 120 mg/kg and 15.75 Gy of fractionated total-body irradiation (TBI) with methotrexate (MTX) given intermittently during a 102-day period to prevent graft-versus-host disease (GVHD). Regimen 2 (22 patients) consisted of the same CY and TBI treatment and a combination of MTX and cyclosporine (CSP) for GVHD prophylaxis. The remaining 75 patients were treated with 17 other transplant regimens. Outcome was compared for patients who were treated with regimen 1, regimen 2, and any other regimen. RESULTS The 5-year probabilities of relapse-free survival (RFS), relapse, and nonrelapse mortality for 126 patients were .23, .57, and .44, respectively. With regimen 1, relapse (.26) was significantly less than for regimen 2 (.70; P = .004) or any other regimen (.76; P = .004). Regimen 1 patients developed more acute GVHD (.67) than regimen 2 patients (.26; P = .02) or patients on other regimens (.41; P = .02), and had increased nonrelapse mortality. Nevertheless, regimen 1 patients had a significantly higher 3-year RFS (.38) than those treated with regimen 2 (.18; P = .04) or any other regimen (.20; P = .05). CONCLUSIONS For patients who received 120 mg/kg CY and 15.75 Gy TBI, relapse incidence was less and survival was better after GVHD prophylaxis with MTX alone than after a combination of MTX and CSP, despite a significantly higher incidence of acute GVHD. The results of treatment with regimen 1 justify future studies of the optimal timing of allogeneic BMT in the treatment of patients with AML.

Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS‐related acute myeloid leukaemia

Allogeneic marrow transplantation using related marrow donors for myelodysplasia (MDS) and acute myeloid leukaemia (AML) arising from MDS results in 35–56% actuarial disease‐free survival. Because the use of unrelated donors has not been well‐characterized, we report on the outcome of 52 patients with MDS or MDS‐related AML consecutively treated between 1987 and 1993 with unrelated donor marrow transplantation. The median age was 33 (range 1–53) years. 33 patients received chemotherapy and total body irradiation and the remainder busulfan and cyclophosphamide. The donors were phenotypically identical at the HLA‐A, B and Dw/DRB1 loci in 34 cases and mismatched for one HLA locus in 17 cases and two loci in one case. Marrow was non‐T‐cell depleted and methotrexate with cyclosporine or FK506 was used for postgrafting immunosuppression. The 2‐year disease‐free survival, relapse, and non‐relapse mortality rates were 38%, 28% and 48%, respectively. One patient who relapsed survives disease‐free after withdrawal of immunosuppressive therapy. 16/19 survivors have a performance status of 90–100%. Patients with MDS in transformation or with AML had a significantly higher risk of relapse than patients with less advanced disease (P = 0.0014). Increased non‐relapse mortality was significantly associated with higher age, longer disease duration before transplant, lower neutrophil count on admission and, unexpectedly, being seronegative for cytomegalovirus. We conclude that the outcome with transplantation using unrelated donors is similar to reported results using related donors and that a meaningful proportion of eligible patients with an otherwise incurable disease may be cured with this treatment. However, mortality from the transplant procedure is high and future studies should focus on reducing toxicity.

Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors.

PURPOSE To determine if an intensive preparative regimen of busulfan (BU), cyclophosphamide (CY), and total-body irradiation (TBI) could improve outcome after marrow transplantation for advanced morphology myelodysplasia (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML]) compared with that obtained with conventional CY/TBI and to analyze prognostic factors for transplantation for myelodysplasia. PATIENTS AND METHODS A phase II study was conducted of 31 patients (median age, 41 years) treated with BU (7 mg/kg), CY (50 mg/kg), TBI (12 Gy), and human leukocyte antigen (HLA)-matched (n = 23) or -mismatched (n = 2) related or unrelated donor (n = 6) marrow transplantation. Results were compared with 44 historical control patients treated with CY (120 mg/kg) and TBI. RESULTS The 3-year actuarial disease-free survival (DFS) rate was similar for the BU/CY/TBI group and the CY/TBI group (23% v 30%, P = .6), but there were trends toward lower relapse rates (28% v 54%, P = .27) and higher nonrelapse mortality rates (68% v 36%, P = .12) among the current patients compared with historical controls. Multivariate analysis showed that a normal karyotype pretransplant and the use of methotrexate as part of posttransplant immunosuppression were associated with improved survival and reduced nonrelapse mortality. Univariate analysis showed significant differences in relapse rates based on marrow source (57% for HLA genotypically matched marrow v 18% for all others, P = .04) and on disease morphology (66% for RAEB-T v 38% for RAEB and CMML, P = .05). CONCLUSION Patients with advanced morphology myelodysplasia tolerated the intensified BU/CY/TBI preparative regimen and reduced posttransplant immunosuppression poorly. Novel transplant procedures are needed to reduce relapse rates without increasing nonrelapse mortality rates. In addition, transplantation before progression to RAEB-T, if possible, may reduce the risk of relapse.

Chronic kidney disease in long-term survivors of hematopoietic cell transplant

We conducted a cohort study to identify risk factors of chronic kidney disease (CKD) among long-term survivors of hematopoietic cell transplant (HCT). We studied 1635 patients transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1991 and 2002, who survived to day +131 after transplant and had serum creatinine measured on at least two occasions after day +131. CKD was defined as a glomerular filtration rate < 60 ml/min/m2 on two occasions separated by at least 30 days between days 100 and 540 post transplant. Cox regression models estimated hazard ratios (HRs) describing associations between demographic data, clinical variables and the risk of developing CKD. A total of 376 patients (23%) developed CKD at a median of 191 days post transplant (range 131–516 days). An increased risk of CKD was associated with acute renal failure (ARF) (HR=1.7, 95% confidence interval (CI) 1.3–2.1), acute graft-vs-host disease (aGVHD) grade II (HR=2.0, 95% CI 1.4–2.9) and grades III/IV (HR=3.1, 95% CI 2.1–4.6) and chronic GVHD (HR=1.8, 95% CI 1.4–2.2). Total body irradiation (TBI) (HR=1.0, 95% CI 0.8–1.3) was not associated with an increased risk of CKD. CKD is relatively common among survivors of HCT. The presence of ARF and GVHD, but not receipt of TBI, appears to be associated with the occurrence of CKD.

Albuminuria in Hematopoietic Cell Transplantation Patients: Prevalence, Clinical Associations, and Impact on Survival

Chronic kidney disease (CKD) is common after hematopoietic cell transplantation (HCT). We prospectively measured the urinary albumin:creatinine ratio (ACR) in 142 patients. Total (intact) monomeric albumin was determined by liquid chromatography of untreated urine samples collected weekly to day 100 after HCT. Albuminuria was defined as ACR (mg/g creatinine) > 30; proteinuria, as ACR >300. Cox and logistic regression analyses evaluated ACR as a risk factor for clinical events. The prevalence of albuminuria was 37% at baseline, 64% at day 100, and 50% at 1 year. Proteinuria occurred in 4% of patients at baseline, in 15% at day 100, and in 4% at 1 year. Characteristics associated with albuminuria include age, sex, donor type, hypertension, and sinusoidal obstruction syndrome (SOS). Albuminuria was associated with an increased risk of acute graft-versus-host disease (aGVHD) and bacteremia, but not acute kidney injury (AKI). Albuminuria at day 100 was associated with CKD at 1 year (odds ratio = 4.0; 95% confidence interval [CI] = 1.1 to 14.6). Nonrelapse mortality (NRM) risk was elevated (hazard ratio = 6.8; 95% CI = 1.1 to 41.5) in patients with overt proteinuria at day 100. Albuminuria occurs frequently after HCT and is correlated with aGVHD, bacteremia, hypertension, and progression of renal disease. Proteinuria at day 100 is associated with an 6-fold increased risk of NRM by 1 year after HCT.