This was a retrospective multicenter study including 44 acute leukaemia patients who have received allogeneic haematopoietic SCT (allo-HSCT) after prior exposure to Gemtuzumab Ozogamicin (GO) + chemotherapy. Median interval between last administration of GO and allo-HSCT was 4.2 (range, 0.8–26.3) months. At time of allo-HSCT, 33 patients were in CR. The majority of patients (n=36) received a reduced-intensity conditioning (RIC) regimen before allo-HSCT. All but one patient received low-dose heparin for veno-occlusive disease (VOD) prophylaxis. With a median follow-up of 15 (range, 1.1–63) months, overall survival and disease-free survival after allo-HSCT were 45% (95% confidence interval (CI), 30–61%) and 38% (95% CI, 24–54%) at 2 years, respectively. The cumulative incidence of grade 3–4 hyperbilirubinemia was 13.5% (n=6), with this being 21% in patients with a short (⩽3.5 months) GO-allo-HSCT interval (n=4/19) vs 8% in all others (P=NS). Overall, the cumulative incidence of VOD was 7% (n=3), with this being 10.5% (n=2/19) in patients with a short GO-allograft interval (⩽3.5 months) vs 4% (n=1/25) for all others (P=NS), and 5.5% (n=2/36) in patients receiving an RIC regimen vs 12.5% for the others (n=1/8) (P=NS). These results suggest that GO-based chemotherapy before allo-HSCT is feasible and does not result in an excessive rate of liver toxicity, especially VOD, after allo-HSCT.
The association of chemotherapy and Gemtuzumab Ozogamicin (GO) is increasingly used for the treatment of CD33+ AML patients, both at the time of diagnosis1 and at the time of relapse.2 GO is classically known to induce a significant liver toxicity, that might increase the risk of veno-occlusive disease (VOD), especially in patients receiving allogeneic haematopoietic SCT (allo-HSCT). The incidence of VOD after allo-HSCT ranges from 0 to 70% and many risk factors have been identified (for example, preexisting liver disease, use of a myeloablative regimen or the use of BU as part of the conditioning regimen and others).3 Larson et al.4 have previously shown that using GO as monotherapy for high-risk leukaemia, increased the risk of grade 3–4 hyperbilirubinemia, with a 5% incidence of VOD. On the other hand, when combining GO and chemotherapy, the incidences of grade 3–4 hyperbilirubinemia and VOD were increased up to 54 and 14%, respectively.5 Interestingly, in the study by Larson et al.4 assessing 200 patients who received GO without undergoing prior or subsequent HSCT (auto or allograft), only 0.9% developed VOD whereas the percentage was increased up to 17% for those patients who received a SCT. Another two relatively smaller studies6, 7 suggested an increased risk of VOD in patients who underwent allo-HSCT within a short interval from GO administration (<3.5 months). Nevertheless, no large series have comprehensively assessed this risk thus far. Here, we analysed the outcome of 44 acute leukaemia patients who have received allo-HSCT preceded by a combination of chemotherapy and GO in the course of their disease.
Patients and methods
This was a retrospective multicenter study which included 44 patients (21 men, 23 women) treated in five French institutions (Nantes, Marseille, Limoges, Angers and Bordeaux), and who have received an allo-HSCT between December 2001 and June 2008. The patients were treated in different therapeutic trials or programs at the corresponding institution. Written informed consent was obtained from each patient and donor. The studies were approved by the local ethical committee and performed according to institutional guidelines.
Criteria of selection
The study included acute leukaemia patients receiving allo-HSCT from an HLA-identical related or unrelated donor, and who have received in the course of their disease at least one dose of GO either as monotherapy or in combination with other chemotherapeutic agents, before undergoing allo-HSCT. Patients receiving a standard (high-dose chemo/radiotherapy) or a reduced-intensity conditioning (RIC) regimen were included. RIC was defined according to the EBMT criteria as the use of fludarabine associated with low-dose TBI (⩽4 Gy), or BU (total dose⩽8 mg/kg), or other immunosuppressive or chemotherapeutic drugs such as melphalan or CY. A total of 44 patients for whom detailed clinical data on toxicities and outcomes were available met these eligibility criteria and were included in the final analysis.
Patients' characteristics and transplant procedures
The median age was 50 (range, 3–67) years. Diagnoses included 41 cases of CD33+ AML, 2 cases of CD33+ ALL and 1 case of isolated CD33+ myeloid sarcoma (MS). Six patients had secondary AML (therapy related, n=2; prior myeloproliferative disorder, n=2; prior myelodysplasia, n=2). Before allo-HSCT, 36 patients (82%) received the MIDAM regimen2 (GO 9 mg/m2 at day 4+Cytarabine 1 g/m2/12 h at days 1–5+mitoxantrone 12 mg/m2/day at days 1–3). In three patients receiving the MIDAM regimen, mitoxantrone was omitted. In another case, the GO dose was reduced to 4.5 mg/m2. The remaining patients received GO 9 mg/m2 and other combinations of chemotherapy. Indications for the GO-based chemotherapy were as follow: first induction therapy, n=3; second induction therapy, n=4; primary refractory disease, n=14; first relapse, n=19; second relapse, n=4. Before allo-HSCT, only one patient developed VOD after receiving GO. In this series, 5 patients received an additional course of consolidation with GO and chemotherapy (9 mg/m2 n=2; 6 mg/m2 n=3) before undergoing allo-HSCT. Of note, 15 patients (34%) received prior auto-HSCT. The median interval between last administration of GO and allo-HSCT was 4.2 (range, 0.8–26.3) months, with 19 patients allografted ⩽3.5 months from GO administration. At time of allo-HSCT, 33 patients were in CR (CR1: n=13 (12 AML, 1 ALL); CR2: n=17 AML; CR3: n= 3 AML) and 11 remained refractory (9 AML, 1 ALL and 1 MS). The majority of patients (n=36; 82%) received an RIC before allo-HSCT, whereas 8 patients received a standard myeloablative regimen. The stem cell source was G-CSF-mobilized PBSC in 26 patients, cord blood in 15, BM in 2 and CD34+ selected PBSCs in 1. In terms of donors, 11 patients received an allograft from an HLA-matched related donor, 1 from an HLA-mismatched related donor, 16 from an HLA-matched unrelated donor and 1 from an HLA-mismatched unrelated donor. As per institutional policy, all but one patient received low-dose heparin 100 IU/kg for VOD prophylaxis, started concomitantly to the conditioning regimen and continued until neutrophil recovery (ANC>500/μl). The single patient who did not receive low-dose heparin for VOD prophylaxis had a history of VOD before allo-HSCT and therefore received defibrotide as per the decision of the attending physician. None of the patients had grade 2 or more hyperbilirubinemia at the beginning of the conditioning regimen for allo-HSCT.
The severity of adverse events was evaluated using the NCI common toxicity criteria version 3 (‘Common Terminology Criteria for Adverse Events’ v3.0 (CTCAE3.0), NCIC, August 2006). VOD was diagnosed using the classical Baltimore clinical criteria.8 Characteristics considered were recipient age, sex, disease features (previous auto-HSCT, remission status at the time of allo-HSCT, cytogenetics risk group: good, intermediate and poor (the two ALL and the MS were included in the high-risk group)),9 prior number of courses of GO (1 or 2), time between GO and allo-HSCT (⩽3.5 months vs >3.5 months; ⩽4.2 months vs >4.2 months), type of donor and allo-HSCT characteristics (conditioning regimen, BU exposure, GVHD prophylaxis, donor type and stem cell source). Standard criteria were used for GVHD assessment. Incidences of transplant-related mortality (TRM), acute and chronic GVHD were calculated. Probabilities of overall survival (OS) and disease-free survival were calculated using the Kaplan–Meier (KM) estimates. The log-rank test was used for univariate comparisons. All potential prognostic factors and those known to influence outcome were included in the multivariate analyses, using Cox proportional hazards with a time dependant variable. Data were computed using the SEM software (SILEX, Mirefleurs, France).
Patients, disease and transplant characteristics are summarized in Table 1. Engraftment was achieved in 34 patients (77%) at a median of 15 (range, 8–43) days after allo-HSCT. The causes of graft failure were advanced disease at time of transplant (4 refractory and 1 CR3 patients who received a PBSCs allograft; RIC regimen with fludarabine/BU/antithymocyte globulin (ATG) in 3 and the FLAMSA regimen in 2) or source of stem cells (5 cord blood transplants; RIC regimen with fludarabine/CY and TBI 2 Gy in 2 and fludarabine/BU/ATG in 2 and a myeloablative regimen with BU/CY in 1). Grade II and grade III–IV acute GVHD occurred in 34 and 20% of the patients, respectively. Chronic GVHD was observed in 27% of the patients (with 8 patients having a limited form and 4 having an extensive one). With a median follow-up of 15 (range, 1.1–63) months for surviving patients, OS and leukaemia-free survival after allo-HSCT were 45% (95% confidence interval (CI), 30–61%) and 38% (95% CI, 24–54%) at 2 years, respectively (Figures 1 and 2). At time of analysis, 22 patients were still alive, whereas 22 patients died. The causes of death included disease progression in 13, 1 invasive fungal infection, 2 cases of severe acute GVHD, 1 chronic GVHD and infection, 3 multiorgan failures, 1 acute respiratory distress syndrome and 1 case of VOD, for an overall incidence of TRM of 20% (95% CI, 8–32%) in this high-risk population. The incidence of grade 3–4 hyperbilirubinemia was 14% (n=6; 95% CI, 4–24%), with this being 16.5% in patients with a short (⩽4.2 months, corresponding to the median interval between last administration of GO and allo-HSCT) GO-allograft interval (n=4/24) vs 10% (n=2/20) in all others (P=NS). In addition, when considering the previously published cutoff of 3.5 months,6, 7 the incidence of grade 3–4 hyperbilirubinemia was 21% in patients with a short (⩽3.5 months) GO-allograft interval (n=4/19) vs 8% in all others (P=NS). Also, in the first 3 months after allo-SCT, OS was not significantly different, when comparing the group of patients with a short (⩽3.5 months) GO-allograft interval vs all others (Figure 3). This incidence was 14% in patients receiving an RIC regimen (n=5/36) vs 12.5% (n=1/8) for the others (P=NS) and 20% in patients receiving 2 prior courses of GO (n=1/5) vs 10.2% (4/39) for all others (P=NS). In all, the incidence of VOD was 7% (n=3), with this being 8.3% (n=2/24) in patients with a short GO-allograft interval (⩽4.2 months) vs 5% (n=1/20) for all others (P=NS), and 10.5% (n=2/19) in patients with a ⩽3.5 months GO-allograft interval vs 4% (n=1/25) for all others (P=NS). The incidence of VOD was 5.5% (n=2/36) in patients receiving an RIC regimen vs 12.5% for the others (n=1/8) (P=NS) and 0% in patients receiving two prior courses of GO (n=0/5) vs 12.8% (n=5/39) for the others (P=NS). Incidence of VOD was 8% (n=2/25) in patients who received a conditioning including BU vs 5% (n=1/19) for the others. The patient who has already presented a VOD after prior GO exposure and who received defibrotide as VOD prophylaxis did not develop VOD after allo-HSCT. Both in univariate and multivariate analyses, no factors were significantly associated with a higher risk of liver toxicity (grade 3–4 hyperbilirubinemia) in this series.
In this analysis, we have focussed on the consequences of prior exposure to GO associated with chemotherapy in terms of hepatotoxicity in patients with CD33+ leukaemias receiving allo-HSCT. Our results suggest that prior treatment combining chemotherapy and GO does not have a significant impact in terms of grade 3–4 hyperbilirubinemia or VOD occurrence after allo-HSCT. The incidences we observed (13.5 and 7%, respectively) are rather comparable to previously published data in allo-HSCT patients who did not receive GO in the course of their disease before allo-HSCT, both in the standard allo-HSCT setting10 and the RIC setting.11 Also, the low incidence of VOD observed in this series compares favourably with that observed in our program in patients who did not receive GO before allo-SCT (4.3% in 484 patients treated within the same period).
Other smaller studies have also reported a relatively low incidence of VOD following allo-HSCT in patients who were pretreated with GO.4, 12, 13, 14, 15, 16, 17 The latter also held true when considering GO as part of the conditioning regimen. Indeed, De Lima et al.18 described the outcome of 52 patients who received a conditioning regimen including fludarabine, melphalan and GO 2 or 4 mg/m2. In the latter study, only one patient experienced a reversible liver VOD and none of the other seven patients previously exposed to GO developed VOD with a median time from last GO dose to allo-HSCT of 8.5 months. Similarly, Bornhauser et al. have recently reported a series of 31 patients who received 2 courses of GO 3 mg/m2 at day −21 and day −14 before allo-HSCT followed by a conditioning regimen including fludarabine, low-dose TBI or melphalan. All patients received low-dose heparin as VOD prophylaxis and only one patient developed VOD.19
Our results demonstrate that a short interval between GO administration and allo-HSCT (<4.2 or <3.5 months), or a higher intensive conditioning regimen do not translate into a higher incidence of liver toxicity, even in heavily pretreated patients, as it is the case for all patients included in our series. However, our results are different from those published in another two smaller studies. In the report by Waldleigh et al.,6 14 adult patients have received GO before a standard myeloablative conditioning regimen including standard dose TBI and CY. In this study, prior exposure to GO translated towards a significantly worsened day +100 OS and a 64% severe VOD incidence. The authors concluded that timing of allo-HSCT in relation to GO exposure may be an important factor for those who developed VOD, as 90% of patients who underwent allo-HSCT 3.5 months or less from GO, developed VOD vs none in the rest of the group. As observed in our series, the dose of GO was not predictive of VOD, suggesting that reducing the GO dose may not reduce the risk of VOD. In the series from Arceci et al.,7 15 paediatric patients have received GO as monotherapy before allo-HSCT. This study did not report about the intensity of the conditioning regimens that were used. In all, 6 patients out of 15 (40%) developed VOD after allo-HSCT.
The systematic use of low-dose heparin for VOD prophylaxis may help in explaining the discrepancies between our findings and the above studies. Indeed, heparin prophylaxis has been already prospectively established to be highly effective in preventing VOD after allo-HSCT both in adult20 and paediatric patients.21 The use of other drugs such as defibrotide may also be effective in this setting and deserves further investigations.22
In our series, more than 50% of the patients received an RIC regimen which is associated with a lower rate of toxicities, including VOD.23 Also, patients usually received GO combined to chemotherapy (mostly as part of the MIDAM regimen2) and with a delayed administration (day 4 after the start of chemotherapy). Delayed infusion of GO at day 4 may allow to reduce CD33 Ag load in the peripheral blood and consequently increases the penetration and efficacy of GO into the BM.24 The latter may help reducing liver penetration of GO allowing for lower toxicity. Currently, the exact mechanisms of GO-related liver toxicity are not yet well elucidated. McDonald25 proposed the term of sinusoidal obstruction syndrome for GO-related VOD because it is more descriptive of the lesions seen in patients. These lesions can associate direct injury of Kupffer cells, which are known to express the CD33 Ag, defective secretion of gluthionyl calicheamicin by hepatocytes leading to accumulation of calicheamicin in hepatocytes and sinusoids and apoptosis of sinusoidal endothelial cells. Thus, reducing calicheamicin accumulation in the liver by increasing penetration in BM may help to decrease liver toxicity.
In all, we conclude that GO-allo-HSCT interval does not appear to be a major determinant for VOD occurrence after allo-HSCT, especially if adequate VOD prophylaxis is applied. Therefore, allo-HSCT can be proposed without an excessive rate of liver toxicity, to those high-risk patients who are in need for transplant despite prior exposure to GO.
Conflict of interest
The authors declare no conflict of interest.
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We thank the nursing staff for providing excellent care for our patients. We also thank the ‘Région Pays de Loire’, the ‘Association pour la Recherche sur le Cancer (ARC)’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’ and the ‘Association Laurette Fuguain’ for their generous and continuous support for our clinical and basic research work.
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Chevallier, P., Prebet, T., Turlure, P. et al. Prior treatment with gemtuzumab ozogamicin and the risk of veno-occlusive disease after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 45, 165–170 (2010). https://doi.org/10.1038/bmt.2009.153
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