The full therapeutic potential of allogeneic stem cell transplantation, through its immunologically mediated graft-versus-tumor effect, in patients with hematologic malignancies is greatly compromised by the occurrence of graft-versus-host disease. Unfortunately, the use of non-selective immunosuppressive agents to reduce the incidence and severity of graft-versus-host disease is associated with severe immune compromise of the host and most likely a greater relapse risk of the underlying malignancy. Many attempts have been made to clinically separate these two effects. A critical overview of the published experience is the focus of this report. As the effector cells responsible for the two reactions are largely unknown, the limited success of the various approaches used is not surprising. A more thorough understanding of the antigenic stimuli involved in the initiation of the two reactions and of the molecular pathways through which the cytotoxic effects of T-cells are mediated is essential for abrogating graft-versus-host disease while preserving the graft-versus-tumor effect.
Background: MEL-ASCT is standard therapy for multiple myeloma (MM) but is associated with severe infections, at times life-threatening. Objective: To determine the risk factors for severe infection (bacteremia, septic shock, colitis, pneumonia) following MEL - ASCT for MM. Materials and Methods: 382 consecutive MM patients (pts) enrolled in our Total Therapy 2 protocol and who received their first MEL - ASCT between 10/1998 and 12/2002 were included. Variables evaluated included age, sex and MM remission status, severity of mucositis and others. Because of the known association between increased body iron stores and infection, pre-ASCT bone marrow (BM) iron stores were also evaluated. The AUC for severe neutropenia (<100 absolute neutrophils (ANC) / mL) was used as a single variable accounting for both the depth and duration of neutropenia. Results: Median age was 56 years (range: 30–76) and 235 pts (62 %) were males. Severe infections developed in 77 pts (20%) including pneumonia (42 pts). Pre-ASCT risk factors for infection by univariate analysis were increased BM iron stores (OR= 3.601; 95%CI 1.795–7.222; p<0.0007) and low platelets counts (OR for -1000 platelets/μL = 0.997; 95% CI 0.994 – 1; p=0.0381). Increased BM iron stores remained significant by multivariate analysis (OR= 3.601; 95% CI 1.795–7.222; p<0.0007). Post-ASCT risk factors that were significant by both univariate and multivariate analysis were severe mucositis (Grades 3–4 by NCI Common Toxicity Criteria) (OR=1.916; 95% 1.093–3.36; p=0.02) and AUC of severe neutropenia (OR= 1.001/unit; 95% 1–1.002; p=0.03). Neither the duration (days with ANC <1000 / mL) nor the depth of moderate neutropenia (AUC < 1000 neutrophils / mL) predicted infection. Conclusion: MM pts scheduled to undergo MEL - ASCT and who have increased BM iron stores, and those who develop severe mucositis and / or prolonged and profound neutropenia following ASCT should be considered at greater risk for developing severe infection. AUC of severe neutropenia is a useful single marker of both depth and duration of neutropenia and should be included in studies evaluating risk for infection in neutropenic pts.
Total Therapy II (TT2), consisting of intensive induction with non-cross resistant VAD, DCEP, CAD (with collection of PBSC) and DCEP.; followed by tandem autotransplants in support of melphalan 200mg/m2; followed by consolidation chemotherapy every 3 months x4 ; followed by interferon maintenance, has complete accrual of 668 patients with upfront randomization to +/− Thalidomide. Collection goal was 20 million CD34+ cells/kg with CAD. This number allows for tandem transplants with support of >5 x 106 CD34 cells/kg, additional cells were stored in case of engraftment problems, additional transplants in the future for relapsed disease and in case of development of MDS. Patient characteristics are outlined in Table 1. 319 patients collected >20 x106 CD 34+ cells/kg with CAD (median 24.9 million, range 20–127), 2 proceeded to second collection with DCEP (median 5.005 million, range 0–10.01. Of this group 310 patients (97%) underwent single and 234 (73%) tandem autotransplant. 135 patients collected 10 – 20 x106 CD 34+ cells/kg with CAD (median 16.35 million, range 10.09–19.93), 13 patients had second collection with DCEP (median 4.92 million, range 1.23–11.68), 5 patients underwent third collection with growth factor (median 2.61million, range 0.12–12.85). Of this group 130 patients (96%) underwent single and 94 (70%) tandem autotransplant. 46 patients collected 5 – 10 x106 CD 34+ cells/kg with CAD (median 7.82 million, range 5.1–9.97), 20 patients had second collection with DCEP (median 9.785 million, range 0.93–27.14), 8 patients underwent third collection with growth factor (median 2.02million, range 0.3–11.8). No patient underwent a fourth collection attempt. Of this group 44 patients (96%) underwent single and 29 (63%) tandem autotransplant. 63 patients collected <5 x106 CD 34+ cells/kg with CAD (median 3.03 million, range 0.01–4.83), 52 patients had second collection with DCEP (median 3.49 million, range 0–21.21), 28 patients underwent third collection with growth factor (median 1.75million, range 0.07–18.99) and 8 patients had a fourth collection attempt with growth factor (median 1.35 million, range 0.22–5.5). Of this group 59 patients (94%) underwent single and 40 (63%) tandem autotransplant. 40 patients collected no CD34+ cells/kg with CAD. 17 patients had second collection with DCEP (median 11.75 million, range 019–36.36), 8 patients underwent third collection with growth factor (median 4.53 million, range 0.11–18.55) and 4 patients had a fourth collection attempt with growth factor (median 2.09 million, range 1.54–12.27). Of this group 25 patients (63%) underwent single and 4 (10%) tandem autotransplant. 53% of patients reached the collection goal with CAD alone. Using additional collection attempts we were able to increase that number to 57% of patients. In the group of the CAD non-collectors additional collection attempts yielded results up to 36 x 106 CD34+ Cells/kg allowing the majority of these patients (> 70%) to proceed to autologous transplant. Table 1: Patients depending on initial collection result with CAD Overall >20* 10–20* 5–10* 0–5* 0* * (x 106 CD34+ cells collected) N 603 319 (53%) 135 (22%) 46 (8%) 63 (10%) 40 (9% Age >65 19% 14% 17% 30% 30% 28% CA 31% 30% 33% 30% 40% 25% Thal Arm 49% 41% 56% 63% 57% 50% CRP >4 8% 7% 10% 7% 8% 10% B2M >4 31% 26% 36% 33% 37% 43% LDH >190 29% 27% 33% 26% 30% 40% BM >30% PC 64% 62% 67% 63% 67% 60%
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