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We have previously shown that patients at high risk of graft-versus-host disease (GVHD) and transplant-related mortality (TRM) can be identified on day +7 following an allogeneic bone marrow transplant (BMT), based on serum bilirubin and blood urea nitrogen levels. One possible approach to reduce the risk of GVHD and TRM, is pre-emptive treatment with T cell antibodies. We report a pilot study testing the feasibility of this approach in 18 high risk patients, with a median age of 41, 83% of whom had advanced disease, undergoing an alternative donor BMT (family mismatched in five and unrelated in 13). The patients received three doses of rabbit antithymocyte globulin (ATG) (Thymoglobuline; Sangstat) 1.25 mg/kg on alternate days, starting at a median interval of 11 days (range 7-13) after BMT. Controls were 20 historical unrelated donor transplants (median age 35, 63% with advanced disease), with a high score from our original publication in 1999. The actuarial 1 year TRM of the ATG-treated patients was 40% compared to 60% for untreated controls (P = 0.06). Severe grade III-IV aGVHD developed in 27% of the ATG-treated patients, and in 55% of the controls (P = 0.08). This study indicates that early pre-emptive treatment of aGVHD in day +7 high risk patients is feasible and may lead to a reduction of aGVHD and TRM. This approach is being tested in a prospective randomized trial.

This is a dose-finding study using foscarnet for CMV prophylaxis after allogeneic bone marrow transplantation (BMT) in 20 high risk patients (unrelated donors, or T cell depleted, and/or advanced disease). Foscarnet was started on day +1 after BMT and continued until day +100. We explored four different dose levels, patients being entered at the lowest dose level until one patient experiences CMV-reactivation, identified as two consecutive positive CMV antigenemias (CMVAg-emia). The four dose levels expressed as mg/kg/day between days 1 and 30 (induction) and between days 31 and 100 (maintenance) were respectively: dose level I = 60/30 (n = 5); dose level II = 120/60 (n = 4); dose level III = 120/90 (n = 5) and dose level IV = 120/120 (n = 6). All patients showed engraftment: PMN > or =0.5 x 109/l at a median interval of 16, 21, 17, 15 days after BMT, and Plt > or =30x10(9)/l on days 19, 16, 17, 17 respectively. CMVAg-emia was seen in 10 patients at a median interval of 53 days post-BMT (range 33-89) with a median of 10 CMV antigen+ cells (range 1-16). There was a dose effect of foscarnet on CMVAg-emia: respectively 4/5 patients (80%), 2/4 (50%), 3/5 (60%) and 1/6 (18%) at dose levels I, II, III, IV (P = 0.1). CMV disease was seen in 3/9 (33%) at dose levels I, II and 0/11 at dose levels III, IV (P = 0. 07). The median number of CMV antigen-positive cells at diagnosis of CMV infection was different: 13 in dose levels I-II and two in dose levels III-IV (P = 0.01). Increased creatininine was seen in 15 patients with a mean of 1.8 mg% (range 1.5-5.7) and was the cause of discontinuation in nine patients (45%). Renal toxicity was reversible in all nine patients. Overall actuarial TRM at 2 years was 31%: 47% for patients at dose levels I-II and 19% for patients at dose levels III-IV. In conclusion, foscarnet exhibits a dose-dependent prophylactic effect on CMVAg-emia, CMV disease and transplant-related mortality with acceptable and reversible renal toxicity.

In the present study, we analyze factors predicting graft-versus-host disease (GvHD) and response after donor lymphocyte infusions (DLI). A total of 100 patients received 593 DLI between June 1990 and December 2000 in a bulk dose (n=14) or in escalating dose infusions (n=86). Patients were analyzed after stratification for type of relapse: (1). molecular relapse (n=6), (2). cytogenetic relapse (n=20), (3). chronic phase of chronic myeloid leukemia (CML) or complete remission of other disease post chemotherapy (n=24), (4). CML in accelerated/blastic phase (n=14), (5). resistant disease not responding to chemotherapy (n=36). The proportion of responders to DLI in these five groups was 100, 90, 75, 36 and 0% (P<0.0001). Factors predicting response by multivariate analysis were type of relapse (P<0.0001), post-DLI GvHD (P=0.005), pancytopenia (P=0.008), and a diagnosis of CML (P=0.04). Acute GvHD (grades II-IV) occurred in 21 patients (21%), and correlated in multivariate analysis with pancytopenia and less than four DLI. Other predictors of GvHD were the number of CD3+cells/infusion and serum levels of gamma-glutamyl transferase (gammaGT). The actuarial probability of treatment-related mortality was 9% for HLA identical siblings and 44% for alternative donor transplants (P=0.006). Response to DLI is predicted by tumor burden and is associated with GvHD and pancytopenia.

We have previously described a scoring system for patients undergoing hemopoietic stem cell transplantation (HSCT) based on day +7 blood urea nitrogen (BUN) and serum bilirubin levels. We have revised that scoring system using a formal multivariate approach based on a training phase (305 patients) and a validation phase (217 patients). Day +7 BUN, serum cholinesterase (CHE), total proteins (TP), gamma glutamyl transferase (gammaGT), donor type and cell dose at transplant were included in the new score. The score distribution identified three groups of patients in the training set (<25, 25-75, >75 percentile of the score) which were classified as low, intermediate and high risk. Their actuarial risk of transplant-related mortality (TRM) at 6 years was, respectively, 12, 38 and 60%. In the validation set the 6 year actuarial TRM was, respectively, 15, 40 and 69%. High risk patients had more graft-versus-host disease (GvHD) (P <0.0001) and lower platelet counts (P <0.0001). This study confirms that GvHD and TRM can be predicted on day +7 after HSCT: pre-emptive GvHD therapy may be one option for high-risk patients and is being tested in a prospective randomized trial. The score for single patients can be calculated on the web site http://213.26.110.20/lrm/day_seven_score.html.

Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications.

We developed a PCR-based method to monitor clonogenic IgH VDJ rearrangement as a possible predictor of relapse in patients with acute B-ALL after allogeneic bone marrow transplantation (BMT). We studied 23 patients at diagnosis, before and after BMT. At the time of BMT, 13 patients were in first complete remission, eight in second complete remission and two in relapse. Four patients were PCR negative before BMT and remained PCR negative also after BMT (-/- pattern). They are still in remission after a median follow-up of 41 months. Nineteen patients were MRD-positive before BMT: three were PCR negative at first determination after BMT (+/- pattern) and maintain remission. Sixteen patients were PCR-positive at first determination after BMT (+/+ pattern): five became PCR negative (+/+/- pattern) (four with chronic graft-versus-host disease (GVHD) and two after donor lymphocyte infusions (DLI)). Nine patients remained PCR-positive (+/+/+ pattern) (four remain in remission, and six relapsed); two patients died before transplant. In conclusion, PCR negative patients before BMT remained negative post-BMT; many pre-BMT positive patients had initial MRD positivity after BMT: 37% of them achieved a molecular remission with cGVHD or DLI.

Serum cholinesterase (CHE) has been reported to be a significant indicator of liver function and prognosis in patients with cirrhosis. On the other hand, liver complications are frequent following allogeneic stem cell transplantation (HSCT). We therefore tested whether CHE was predictive of graft-versus-host disease and outcome in HSCT recipients. We studied 689 patients receiving a HSCT from an HLA-identical sibling (SIB) (n = 511), an alternative donor (n = 173) or a syngeneic twin (n = 5). Acute graft-versus-host disease (GVHD) was scored as 0-I, II, III-IV in 325 (47%), 279 (41%), and 85 patients (12%) respectively; 190 (28%) patients died of transplant-related complications (TRM). On day -7 the median CHE serum level was comparable in patients who either survived or died of TRM (5900 IU/l). On day 0, serum CHE levels were respectively 2310 and 2120 IU/l (P = NS) indicating the impact of the conditioning regimen. On day +7 after HSCT, the median level for surviving patients was 2598 IU/l vs 2309 IU/l for patients who subsequently died (P = 0.0002), on day +21 CHE levels were respectively 3348 vs 2528 IU/l (P < 0.00001), on day +50, 3575 vs 2358 IU/l (P < 0.00001) and on day +100 4193 vs 2729 IU/l (P < 0.00001). CHE levels on day +50 strongly correlated with aGVHD (3803 vs 3070 vs 1933 IU/l for patients with GVHD grade 0-I, II, and III-IV, respectively (P < 0.00001) and relapse (3569 for patients relapsing vs 3115 IU/l for patients not relapsing, P = 0.0006). In conclusion, (1) serum cholinesterase is a simple and reliable marker of acute GVHD and transplant-related complications; and (2) high CHE levels on day +50 predict relapse. If confirmed, the latter patients may be eligible for early reduction of immunosuppressive therapy.

Preparative regimens without total body irradiation (TBI) have been reported for alternative donor hemopoietic stem cell transplants (HSCT). Between 7 September 1994 and 7 June 1999 48 patients with advanced hematologic malignancies were conditioned with thiotepa (THIO) 15 mg/kg, cyclophosphamide (CY) 150 mg/kg and antithymocyte globulin (ATG). Donors were HLA mismatched family members (1-2 antigens) (FAM) (n = 24, median age 31 years) or HLA matched unrelated donors (UD) (n = 24, median age 34 years). GVHD prophylaxis was cyclosporine and methotrexate. Stem cell source was peripheral blood (n = 8) or bone marrow (n = 40). Hematologic recovery was seen in 42/46 (91%) evaluable patients and complete chimerism in 31/37 patients (85%). Acute GVHD grades III-IV were seen in 10/46 patients surviving 10 days (21%) and extensive chronic GVHD in 2/36 patients surviving 100 days (5%). Twenty-six patients died (54%), eight of recurrent disease (17%) and 18 of transplant-related complications (37%): main causes of TRM were GVHD (15%), infections (15%) and graft failure (4%). Twenty-two patients (46%) survive with a median follow-up of 877 days (287-1840). The actuarial 3-year survival is 49% for FAM and 42% for UD transplants. Results obtained with this regimen in unrelated grafts for advanced CML (n = 15) were not significantly different when compared to 21 concurrent UD grafts for advanced CML prepared with CY-TBI. In conclusion, the combination of THIO-CY-ATG allows engraftment of alternative donor hemopoietic stem cells. Results are similar when using unrelated matched donors or partially mismatched family donors, and not significantly different when compared to patients conditioned with CY-TBI.

We investigated bone marrow (BM) and circulating (PB) hematopoietic progenitor cells in 37 normal donors and in 25 patients 1 to 8 years after successful allogeneic bone marrow transplant. At the time of testing, transplanted patients had normal blood counts and bone marrow cellularity. By flow cytometry, BM CD34+ cells were found to be three- to four-fold decreased in transplanted patients compared to normal donors, while the number of PB CD34+ cells was the same as in normal donors. Using a methylcellulose colony assay, primary BM colony-forming cells (CFU-GM) were decreased 2.1-fold, whereas PB CFU-GM were only marginally decreased. In a long-term culture initiating cell (LTC-IC) assay, an eight-fold decrease of early progenitor cells was observed in the marrow of transplanted patients compared to normal donors, and a five-fold decrease was documented in peripheral blood. We found that the BM LTC-IC cell number correlated with concurrently determined BM CD34+ cells and committed progenitor cell number (measured as CFU-GM) and with PB LTC-IC number, but not with PB CFU-GM and CD34+ cells. We conclude that marrow and circulating early stem cell compartments, as measured by the LTC-IC assay, are greatly and permanently depressed following bone marrow transplant. The correlation between BM and PB LTC-IC indicates that the enumeration of circulating LTC-IC can be used as a measure of the stem cell compartment in the bone marrow after transplant. It seems that the deficiency of the most immature progenitor cells persists forever after successful bone marrow transplant; this means that a complete hematopoietic reconstitution can be sustained by a reduced stem cell pool.