We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III-IV organ damage, engraftment failure or death within 30 days. 'Response' was engraftment and remission (CR) on day þ 30. We sought to determine the GO dose (2, 4 or 6 mg m À2 ) giving the best tradeoff between toxicity and response. All patients were not candidates for myeloablative regimens. Treatment plan: GO (day À12), fludarabine 30 mg m À2 (days À5 to À2), melphalan 140 mg m À2 (day À2) and HSCT (day 0). GVHD prophylaxis was tacrolimus and mini-methotrexate. Diagnoses were AML (n ¼ 47), MDS (n ¼ 4) or CML (n ¼ 1). Median age was 53 years (range, 13-72). All but three patients were not in CR. Donors were related (n ¼ 33) or unrelated (n ¼ 19). Toxicity and response rates at 4 mg m À2 were 50% (n ¼ 4) and 50% (n ¼ 4). GO dose was de-escalated to 2 mg m À2 : 18% had toxicity (n ¼ 8) and 82% responded (n ¼ 36). 100-day TRM was 15%; one patient had reversible hepatic VOD. Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m À2 can be safely added to fludarabine/melphalan, and this regimen merits further evaluation.
Most patients (pts) transplanted with active myeloid leukemias will relapse after HSCT. Intensity of the conditioning regimen is an important component of disease control. We hypothesized that GO could safely increase the anti-disease activity of FM, and investigated this hypothesis in the trial reported here. Patients and Methods: Objective: to determine the dose of GO with the lowest toxicity (tox), and the highest response probabilities. Tox: grade 3–4 organ tox, engraftment failure or early death (ED; first 30 days post HSCT). Response was defined as no tox, engraftment, and remission (CR) on day +30. Trial was designed with GO doses of 4, 6 and 9 mg/m2 but given tox observed at 4mg/m2, doses 6 and 9 mg/m2 were not used and dose 2mg/m2 was added. Eligible were pts aged 12–75 years, not candidates for high-dose regimens or with high-risk CD33+ disease. Treatment: GO 2 or 4mg/m2 day -12, F 30mg/m2 (days -5 to -2), M 140mg/m2 (day -2); HSCT day zero. ATG was added in unrelated (UD) HSCT. Graft-versus-host disease (GVHD) prophylaxis: tacrolimus and mini-methotrexate (5mg/m2 day+1,+3,+6,+11). GO was given on day -12 to minimize probability of delaying engraftment. We treated 52 pts, median age 53 yrs (13–72), with AML (n=47), MDS (n=4) or blast crisis CML(n=1). Disease status at HSCT: CR (n=3),induction failure (n=15), first/second relapse (n=33), untreated MDS (n=1). 18 pts had a previous HSCT (allogeneic, n=11 or autologous, n=7). At study entry, median number of bone marrow blasts was 17% (0–95%); 33% of the pts had circulating blasts, 4 pts were FLT3 positive and 38% had poor prognosis cytogenetics. Median blast CD33 expression: 89% (22.5–99.6). Donors: related (n=33) or UD (n=19). Stem cell source was peripheral blood (n=43) or bone marrow (n=9). Results: Median day 30 donor cell chimerism was 100%. Median time to ANC> 500/mm3 was 13 days. Eight pts received GO at 4 mg/m2; 2 died early (due to pneumonia and renal failure) and 2 developed gd III gastro-intestinal and renal tox. 44 pts were then treated at 2 mg/m2: 3 pts died of regimen-related tox (2 ED due to pulmonary bleeding and sepsis, and 1 death within the first 100 days due to pneumonia, renal failure/TTP/HUS). 100-day treatment-related mortality (including 2 deaths due to aGVHD and 1 due to infection) was 15% (n=8). Tox included reversible gd III-IV bilirubin (n=2), transaminase elevation (n=5), moderate hepatic VOD (n=1) and gd I-II GI tract (n=39). CR rate was 90%; 1 pt failed to respond. Gd II-IV and III-IV aGVHD rates were 44% and 23%, respectively, and 58% developed cGVHD. Median follow-up is 9 months (2.5–36) for surviving pts (n=29); 17 pts have relapsed. Median event-free-survival (EFS) is 3.8 mos. Median EFS of a historic control group treated with FM140 (n=36) was 2.2 mos (Figure). Tox of GOFM is similar to that documented by our group with FM140 mg/m2 in a somewhat better prognosis population.(de Lima et al. Blood.2004; 104:865–72) Conclusion: GO 2mg/m2 can be safely added to FM, and may improve the anti-leukemic efficacy of the regimen. EFS - patients with active disease at HSCT EFS - patients with active disease at HSCT
Objective: To assess the clinical and prognostic implications of the timing of acute GVHD (aGVHD). Introduction: Traditionally, the syndrome of acute GVHD has been chronologically defined as GVHD occurring before day 100. It has become increasingly clear that this syndrome can occur after day 100, which raises the question of historical misclassification of aGVHD occurring after day 100 (“late aGVHD”) as chronic GVHD. On the other hand, timing of GVHD could have prognostic implications and the case in hyperacute forms of GVHD are an example. In this study, we redifine aGVHD based on clinical manifestations and we evaluate risk factors as well as clinical and prognostic differences between late aGVHD and GVHD before day 100 (“classic aGVHD”). Methods: Retrospective evaluation of records and database on all matched sibling transplants (n= 128) performed at UT MDACC from 1/00 to 2/02. Results: A total of 47 patients (37%) had “classic” aGVHD and another 67 (52%) were classified as chronic GVHD (cGVHD) in our database. Upon review of medical records, 30/67 patients (45%) were found to have late aGVHD, and the remainder true cGVHD. Of these 30 patients, 9 had aGVHD progressing through day 100 and were reclassified as classic aGVHD. The remainder 21 had newly diagnosed late aGVHD. We evaluated risk factors for developing late aGVHD in patients who were alive at day 100. Only a later engraftment (ANC>500 beyond day 12) was associated with a higher incidence of late aGVHD, while age, gender, malignancy, disease status at transplant, type of preparative regimen (nonmyeloablative versus others), bone marrow vs peripheral blood or CD3,4 or 8 infused did not impact the incidence of late acute GVHD. Compared to classic aGVHD, the late group had a significantly higher proportion of grade 2–4 GVHD (85 vs 61%, p= 0.03) with similar grade 3–4 aGVHD (29 vs 27%, p= 0.5). Skin and GI involvement, as well as isolated elevation of the alkaline phosphatase were more common manifestations of late aGVHD. There was a trend to better response (CR/PR) to first line immunosuppression in patients with late aGVHD (81 vs 63%, p= 0.13), but this was not statistically significant. The overall survival (OS) and non-relapse mortality (NRM) since the diagnosis of GVHD were substantially better in patients with late aGVHD (OS 70 vs 29%, p= 0.01; NRM 16 vs 39%, p= 0.06). Finally, the NRM of patients with chronic GVHD prior to reclassifying patients with late aGVHD (n= 67) was 28% at 2 years. When patients with late aGVHD were excluded, the NRM at 2 years for the remainder 37 patients with chronic GVHD was 20% (p= 0.3). Conclusions: 1- The current chronological definition of acute GVHD may lead to misclassification of late aGVHD as chronic GVHD. This could have implications in interpreting the current knowledge and literature on GVHD, 2- There was a trend to higher NRM in the chronic GVHD group prior to reclassifying cases of late aGVHD, althought the difference was not statistically significant, 3-Patients with late aGVHD share similarities with those with classic aGVHD, although there seems to be a trend to better response to therapy and better survival in patients developing aGVHD beyond day 100. Thus, timing of aGVHD may affect its outcome.
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