A. Fassas

18F-Fluorodeoxyglucose Positron Emission Tomography Contributes to the Diagnosis and Management of Infections in Patients With Multiple Myeloma: A Study of 165 Infectious Episodes

PURPOSE Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM). PATIENTS AND METHODS The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome. RESULTS One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET. CONCLUSION In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.

Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: a study of 367 myeloma patients

We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/μl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707–4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005–2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019–2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720–4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081–2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 μ/l (OR=1.129; 95% CI 1.039–1.226; P=0.0069 and OR=1.127; 95% CI 1.038–1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.

Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model.

Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4–6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080–2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065–2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.

Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483–487.

Preceding chemotherapy, tumour load and age influence engraftment in multiple myeloma patients mobilized with granulocyte colony-stimulating factor alone

Haematopoietic growth factors, especially granulocyte colony‐stimulating factor (G‐CSF), are frequently utilized alone for peripheral blood stem cell (PBSC) procurement to avoid the morbidity associated with high‐dose chemotherapy (HDT). Moreover, the cytotoxic agents used may not be the most optimal therapy for the malignancy. It also makes scheduling of apheresis easier. Factors having an impact on PBSC procurement and engraftment after HDT were analysed in 117 multiple myeloma patients mobilized with G‐CSF (10–16 µg/kg, median 12 µg/kg) alone using Cox regression analysis. A median of 6·2 × 106 CD34 cells/kg (range 0·6–34·1) were procured during leukapheresis and a median of 2·5 × 106 CD34 cells was infused after the first HDT (range 0·3–23·9). The only factor significantly affecting optimal PBSC procurement was duration of preceding conventional chemotherapy (P = 0·002). Granulocyte recovery was prompt in almost all patients, 75% of whom attained a granulocyte count of 0·5 × 109/l by day 13 (median 11, range 7–19). However, platelet recovery to both 20 × 109/l (median 12 d, range 8–50+) and 50 × 109/l (median 20 d, range 7–205+) varied widely. On univariate analysis, factors influencing platelet recovery were the number of CD34 cells/kg infused, age, β2‐microglobulin levels, response to preceding therapy, bone marrow plasmacytosis and duration of prior therapy. Factors attaining significance on multivariate analysis included number of CD34 cells/kg infused (P = 0·007), β2‐microglobulin levels (P = 0·0001), most probably representing disease load, and age (P = 0·002). Patients with high tumour burden, i.e. β2‐microglobulin levels > 2·5 mg/l, probably benefit from chemotherapy for mobilization both in terms of cytoreduction and adequate stem cell mobilization resulting in accelerated engraftment.

Recovery from neutropenia can be predicted by the immature reticulocyte fraction several days before neutrophil recovery in autologous stem cell transplant recipients

The duration of neutropenia (absolute neutrophil count (ANC) ⩽100/μl) identifies cancer patients at risk for infection. A test that precedes ANC⩾100/μl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC⩾100/μl in 99% of patients after the first Mel-ASCT by (mean±s.d.) 4.23±1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11±1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count⩾100/μl to the time to ANC⩾100/μl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC⩾100/μl.

Lymphomatoid granulomatosis following autologous stem cell transplantation.

Lymphomatoid granulomatosis (LYG) is a rare angiodestructive lymphoproliferative disorder (LPD) of uncertain etiology, with prominent pulmonary involvement. Recent studies indicate that LYG is an Epstein–Barr virus (EBV)-associated B cell LPD with large numbers of background reactive T lymphocytes (T cell-rich B cell lymphoma). Although the disease frequently, but not exclusively, occurs in various immunodeficiency states, it has not been reported in association with the transient immunosuppression following autologous bone marrow/peripheral stem cell transplantation (ABM/PSCT). We describe a patient who developed lymphomatoid granulomatosis of the lung approximately 2 weeks after high-dose chemotherapy and autologous peripheral stem cell transplantation for multiple myeloma. Although molecular studies showed no evidence of EBV genome in the biopsy material, the serologic profile with high IgM titers was suggestive of primary EBV infection. Complete radiologic remission occurred following reconstitution of the patient’s immune response after a 2-week course of ganciclovir treatment. Despite the apparently low frequency of LPD (both LYG and EBV-associated post-transplant lymphoma) in the ABMT setting, we believe that it should be considered in the differential diagnosis of patients whose clinical course following ABMT is complicated by fevers, in the absence of an identifiable infectious process.