ALBERT

Description: Routine use of myeloid growth factors (GF) after allogeneic HSCT from marrow (BMT) or blood (BSCT) results in faster neutrophil recovery but no survival benefit. Registry data suggest that G-CSF administration after allogeneic BMT influences outcome adversely (Ringdén et al. J Clin Oncol2004;22: 416–23). GM-CSF (Anasetti et al. Blood1993;82Suppl 1: 454a) as well as G-CSF (Schriber et al. Blood; 1994:84:1680–4) administration after unrelated donor BMT has been shown to cause higher treatment-related mortality (TRM) and poorer survival. After having noted an apparent increase in TMA after allogeneic HSCT for acute lymphoblastic leukemia (ALL), we reviewed the course of 10 ALL patients (32–53 y, median 40) allografted from HLA-matched siblings in first remission (n=9) or relapse (n=1) after uniform conditioning with 60 mg/kg etoposide and 1320 cGy total-body irradiation (TBI) in 6 fractions. 9 received G-CSF-mobilized BSCT and 1 BMT. 6 were allografted on a study (ECOG 2993/UK MRC ALL 12) that mandated GM-CSF administration from day 0. The other 4 received no GF in accordance with our standard practice of not using myeloid GF post-allograft. All were scheduled to receive cyclosporine, and 15 mg/m2 MTX on day 1 and 10 mg/m2 MTX on days 3, 6 and 11. 8 patients received all 4 doses of MTX, 1 (not on GM-CSF) received 3 doses, and 1 (on GM-CSF) received only the first dose. TMA characterized by elevated LDH (2–12x increase from baseline), schistocytosis, and variable renal dysfunction (1.7–2.7x increase in creatinine from baseline) was seen in 5 patients; all on GM-CSF (5 of 6 GM-CSF recipients vs 0 of 4 not getting GM-CSF; P=0.053). The only GM-CSF recipient not developing TMA had received only 1 dose of MTX. Thus all 5 patients getting GM-CSF and full-dose MTX developed TMA compared with none of the other 5 (P=0.012). The occurrence of TMA was not associated with grossly elevated cyclosporine levels, required cyclosporine cessation in 4 patients all of whom also underwent plasmapheresis, and contributed to death in 2. Because of this safety concern, we have stopped GF administration after allogeneic HSCT even in patients on ECOG 2993. It is unclear whether this toxicity is attributable to GM-CSF through endothelial activation, the combination of GM-CSF and MTX, or the combination of GM-CSF and MTX in this particular clinical setting (ALL treated with high-dose MTX a few weeks before HSCT or high-dose etoposide-TBI conditioning). While MTX is known to be associated with TMA, we have not seen a similar trend in other diseases where patients have received MTX after the allograft but have not received GF. The ECOG-MRC study also may not be able to answer this question readily as a number of centers have used G-CSF instead of GM-CSF or no GF at all. Our data indicate that this association requires retrospective review of patients who have already been treated, and, in combination with other observations, suggest that not only have myeloid GFs failed to improve the outcome of allogeneic HSCT, but safety concerns continue to cloud their routine use in this setting. Additional data are required to clarify the influence of GF use on the outcome of allogeneic HSCT. For the moment, the use of myeloid GFs should probably be confined to patients experiencing delayed engraftment after allogeneic HSCT.

Description: FDG PET scanning provides useful information that is now being integrated into treatment algorithms for patients with lymphomas. Its use in relation to allogeneic transplantation has not been assessed. We have performed a prospective study to assess the role of PET scans in directing immune manipulation (withdrawal of immune suppression and donor lymphocyte infusions (DLI)) following reduced intensity transplants (RIT) in patients with lymphoid malignancies. Methods: All patients referred to University College Hospital from May 2002 with lymphoid malignancies, suitable for RIT were invited to participate. Patients had PET and CT scans pre-RIT and at 3, 6, 9, 15 and 24 months post RIT. Patients were conditioned with fludarabine and melphalan and in vivo T cell depletion with alemtuzumab. Ciclosporin was given from day −1 to 3 months after RIT. Initial management for positive imaging was withdrawal of immune suppression. DLI was subsequently given to patients who progressed or relapsed at escalating doses of 1 x 106/kg T cells up to 1 x 108/kg. Patients with active GVHD were excluded from DLI. Results: 29 patients, median age 44 years (range 20 to 64 years) entered the study; 24 (6 Hodgkin lymphoma (HL), 2 Mantle cell (MC), 16 Non-Hodgkin Lymphoma (NHL)) are evaluable with 〉 3 months follow-up. 13 of 24 had positive PET scans before RIT, 9 had negative scans and 2 were not scanned before RIT. Of the 13 patients who had positive PET scans, there were 3 transplant related mortalities: CMV pneumonitis (n=1, HL), severe GVHD (n=2, NHL). The 10 remaining patients with positive PETs pre-RIT have a median 10.5 months follow up (range 6 to 24 months). 9 of 10 patients had a response to RIT (7CR and 2PR). Subsequently 5 of these 10 have relapsed/progressed at 6 to 9 months from RIT. Two were treated by withdrawal of immune supression. Both developed GVHD and died of progressive disease. 3 were treated with DLI. One patient (NHL) responded 3 months after 1 x106/kg, one (MC) after 1 x 107/kg and the third (NHL) showed a CR following both 1 x 107/kg and rituximab given for immune cytopenia. The remaining 5 patients (1HL, 4NHL) with positive pre-RIT PET scans remain in remission a median of 9 months (range 6 to 15 months) after RIT. One of 9 patients (NHL) with negative pre-RIT PET scans had progression of disease at 9 months, treated with escalating DLI up to 1 x 107/kg with no response. The remaining 8 patients with negative pre-RIT PET scans have remained in CR a median of 9 months (range 3 to 24 months) from RIT. One patient who did not receive pre-RIT scan died at 9 months of GVHD without evidence of disease progression. The second progressed at 12 months and is awaiting biopsy. 6 patients had nodes on CT scan of unclear significance, with negative PET scans. One of these patients has subsequently relapsed. The remaining patients continue in CR. 3 patients have had positive PET scans and received DLI 3 to 6 months before positive CT findings. This study suggests that PET imaging provides additional information beyond that available from CT scanning aiding patient management including earlier intervention (n=3) and deferring unnecessary treatment (n=6). 3/4 patients receiving DLI have responded. Positive PET scanning pre-RIT was associated with inferior outcome but does not preclude CR (6/13). Further follow-up and larger event numbers are required to establish the role of PET imaging in modulating treatment following RIT in patients with lymphoid malignancies.

Description: Despite impressive primary response rates relatively few patients with multiply relapsed or refractory Hodgkin lymphoma (HL) are ultimately cured with conventional chemotherapy. The application of allogeneic stem cell transplantation has historically been limited in this group by high transplant related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. Reduced intensity transplantation (RIT) approaches enable durable engraftment of allogeneic stem cells with a low spectrum of toxicity, but graft-versus-host disease (GvHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion (TCD), using alemtuzumab, has been shown to reduce the incidence of GvHD. However, this approach potentially adversely impacts on disease response by abrogating GvL activity. To explore the impact of TCD in HL we have compared the results in 89 recipients of a RIT enrolled in 2 prospective studies based on conditioning with the same combination of fludarabine (30mg/m2 x 5) and melphalan (140 mg/m2). The studies differed in GvHD prophylaxis. The United Kingdom regimen (MF-A, n=49) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (MF, n=40) used cyclosporin A plus methotrexate. There were no significant differences in age (median 32 versus 35 years), sex or histological subtype (nodular sclerosis in 86% versus 88%). Median follow-up in surviving patients is 826 (MF-A) versus 376 (MF) days. In those with matched sibling donors use of alemtuzumab resulted in a trend towards a lower incidence of acute GvHD (29% versus 46% at day 180, P=0.09) and significantly less chronic GvHD (10% versus 57%, P=0.0003). This was associated with a trend towards lower TRM in the MF-A group (actuarial 2 year TRM 17% versus 33% for MF, P=0.06), but no apparent excess of relapse/progression (actuarial 2 year relapse risk 49% for MF-A versus 68% for MF, P=0.16). In this sibling transplant cohort both overall and event-free survival were superior in the MF-A group (actuarial 2 year OS 72% versus 48%, P=0.04; EFS 47% versus 19%, P=0.009). Sixteen patients in the MF-A group and 10 in the MF group received donor lymphocyte infusions (DLIs) to achieve disease control. Nine (8CR, 1PR) of the former, and 6 (3CR, 3PR) of the latter achieved a response. On univariate analysis of the entire cohort chemo-sensitivity significantly influenced relapse risk (p=0.01), OS (P=0.01) and EFS (P=0.003). TCD significantly improved EFS (P=0.01) despite an excess of unrelated/mismatched donors (18 versus 3, P=0.001) and patients who had failed a prior autograft in the MF-A cohort (44 versus 29, P=0.03). Prior autograft or donor source had no significant influence on TRM, relapse, OS or EFS. More patients were chemo-sensitive prior to RIT in the MF-A group (36 versus 20, P=0.03) but TCD retained independent positive prognostic significance for EFS in multivariate analysis (P=0.02; Hazard ratio 0.69(0.51–0.93)), as did chemo-sensitivity (P=0.01). In conclusion, alemtuzumab significantly reduced GvHD without resulting in an apparent impact on disease relapse. Both groups often required DLIs to achieve tumor control and the response rates support a significant GvL activity.