ALBERT

Description: Introduction: The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry. Methods: Patients with newly diagnosed myeloma eligible for ASCT received PAD (bortezomib 1.3mg/m2 days 1, 4, 8, 11; doxorubicin 9mg/m2 days 1-4 and dexamethasone 40mg days 1-4 (and days 8-11 and 15-18 for the first cycle only)) for up to 6 cycles (minimum of 4). Bortezomib was initially given intravenously (IV), but once approved this was switched to sub-cutaneous (SC). Those failing to achieve PR were offered salvage therapy off protocol. All others had peripheral blood stem cell (PBSC) mobilisation using cyclophosphamide + GCSF, followed by MRD assessment on bone marrow aspirates using multi-parameter flow cytometry. Depending on disease response, patients were then stratified to ASCT (PR) or no further treatment (≥VGPR). Responses were assessed using International uniform response criteria (Durie 2006) by intent-to-treat and toxicity scored according to CTCAE version 4.0. High risk disease was defined by the presence of one or more adverse FISH lesions (t(4;14), t(14;16), t(14;20), del(17p13), +1q21) as described in the MRC Myeloma IX trial. Results: Between March 2011 and January 2014, 153 patients were enrolled (median age of 55, range 28-71 years). 139 (91%) received between 4-6 cycles of PAD. The majority (135, 88%) received SC only bortezomib and 18 (12%) received at least 1 cycle IV. The overall response rate to PAD was 81% with 46% achieving ≥VGPR (sCR: 6 (4%), CR: 13 (8%), VGPR: 51 (33%), PR: 54 (35%)). FISH data was available for 122 patients, 91 (75%) patients were standard risk and 31 (25%) were adverse. Responses were similar irrespective of ISS or genetic risk (standard, ≥VGPR 44%, PR 34%; adverse, ≥VGPR 55%, PR 29%). MRD results are currently available in 70 of the 124 patients achieving PR post PBSC harvest. Of this group 41 achieved ≥VGPR post-harvest (22 MRD+ and 19 MRD-) and hence did not proceed to ASCT, 13 patients achieved CR of which 8 were MRD negative. Toxicity was as expected for PAD and predominantly haematological. Notably the incidence of neuropathy was lower than that previously reported with IV bortezomib. Grade 3-4 events were: neutropenia: 18%; thrombocytopenia 7%. Grade 2-4 peripheral neuropathy was reported in 27% compared to 40% in the HOVON-65/ GMMG-HD4 Trial using IV bortezomib. Grade 1-2 neuropathy was similar for patients who received IV (55.6%) or SC (60%) bortezomib; however only 7% of patients receiving SC bortezomib developed grade 3 neuropathy compared to 28% with the IV route. Conclusions: SC PAD is a highly effective induction regimen for patients with newly diagnosed myeloma achieving a ≥VGPR of 46%. Of the 41 patients achieving ≥VGPR post-harvest with MRD result available, 46% were MRD negative. Response rates were similar across ISS and with adverse FISH. The use of SC bortezomib improved tolerability and substantially reduced neurotoxicity. ISRCTN no: 03381785. Disclosures Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.

Description: Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Description: Recommended first-line therapy for patients with chronic phase (CP) CML is imatinib mesylate (IM). Although IM induces complete cytogenetic responses (CCR) in the majority of patients, disease often remains detectable by Q-RT-PCR, likely reflecting stem cell persistence. Furthermore, primary and acquired resistance to IM have led to concerns about response durability. Allogeneic stem cell transplantation (SCT) remains the only curative option and with reduced intensity conditioning (RISCT) is less toxic and may be offered to a broader patient group. Our novel approach used IM to establish disease control (CCR) in patients with newly diagnosed CP CML prior to RISCT (fludarabine/melphalan/MabCampath). Prophylactic escalating DLI was given for residual disease. 18 patients (4 centres) were recruited between 2001 and 2006. Of these, 3 received myeloablative SCT, 2 for progression to blast crisis prior to SCT and the third for failing to reach a major cytogenetic response. 15 patients with a median age of 39y (21–56y) received sibling RISCT. Hasford scores were 38% low, 54% intermediate and 8% high risk. EBMT risk scores were 1–2 (13 patients) and 3–4 (2 patients). 5 patients required IM dose escalation to achieve CCR prior to RISCT. Follow-up data extends to a median of 31 (12–61) months (m) post RISCT. The RISCT procedure was well tolerated with rapid engraftment and short in-patient stays. 53% had infective episodes post RISCT, including CMV reactivation (86% patients at risk), EBV+ post transplant lymphoproliferative disease (2 patients) and PCP (1 patient). 1 patient developed aGvHD (grade III) and 8 cGvHD (6 limited, 2 extensive). DLI was given to 13 patients (87%), 6 for elevated Bcr-Abl, 4 for mixed chimerism and 2 for both. The median total dose was 0.65 × 107CD3+cells/kg (0.1–6.65 × 107cells/kg) in a median of 2 infusions. GvHD was seen in 6 of 12 patients receiving DLI (50%). IM was required in 4 patients with residual disease and all discontinued IM once disease control was re-established (4–13m of IM). 1 of 15 transplanted has died (at 12m with GvHD and infection). Of surviving patients median Bcr-Abl measurements fell as follow-up progressed. 8 patients currently have sustained undetectable Bcr-Abl. 7 of these 8 received DLI, the other had GvHD. The interval between last DLI and first proof of disease eradication was median 2m (range 1–28m). Only 2 of these 8 patients received IM post-transplant. In this study, the patients receiving RISCT were in early CP with a CCR to IM. It is likely that the majority would have maintained CCR if not offered transplantation. However the number of patients who achieved undetectable Bcr-Abl following RISCT and DLI compares favourably with the response expected with IM alone. The patients have tolerated the transplant procedure well and are currently off all treatment for CML. Regular monitoring remains necessary, however if relapse occurs it should be DLI responsive. Currently IM is the accepted first line therapy in the majority of patients however we would highlight the importance of RISCT in selected groups and believe our approach is effective and well tolerated.

Description: Inclusion of CAMPATH-1H as part of a Fludarabine/Melphalan conditioning regimen is effective at preventing GVHD and reducing non-relapse mortality (NRM)following allogeneic stem cell transplantation. However, these benefits are offset by high rates of infection and potentially a loss of graft-versus-tumor effects. When used at a total dose of 100mg, CAMPATH-1H antibody can still be detected at levels in excess of those required to induce ADCC for several weeks. We reasoned that a reduction in the dose of CAMPATH-1H would permit improved immune reconstitution post-transplantation. We report here the analysis of a national, multi-center trial in which the total dose of CAMPATH-1H was reduced step-wise in separate cohorts from 60mg to 20mg prior to HLA-identical sibling transplantation (n=106). Eligibility criteria included patients with haematological malignancies who were aged 18–65, who had a life expectancy 〉3 months and who were not suitable for standard myeloablative conditioning. Primary endpoints included PK data, chimerism, NRM and incidence of GVHD or infection. The study received IRB approval and all patients gave informed consent. Four total doses of CAMPATH-1H were tested in consecutive cohorts: group 1, 60mg split between d-2 and d-1 (n=26); group 2, 40mg split between d-2 and d-1 (n=27); group 3, 30mg d-1 (n=28); and group 4, 20mg on day -1 (n=25). 97/106 patients recruited to the study are evaluable with a median follow up of 12 months. Median age was 50 (range 19–64). No major differences were identified in patient characteristics between each cohort. 1-year OS and PFS for the whole population was 80.8% and 67.2% respectively. Peak CAMPATH-IH levels (ug/ml) measured by ELISA on day 0 (n=5 each group) were 7.7 ±1.1 in group 1, 4.3 ±0.7 in group 2, 4.9 ±0.8 in group 3 and 2.7± 0.7 in group 4 (p

Description: Autologous stem cell transplantation (ASCT) remains the treatment of choice for patients (pts) with diffuse large B-cell lymphoma (DLBCL) that relapse after first line chemotherapy (CT). Nevertheless, the impact of the use of the anti-CD20 monoclonal antibody (Rituximab®) (RTX) with combination CT on the ulterior results of the transplantation procedure has to be determined. One of the main factors affecting survival after ASCT is a short first remission duration. This study was designed to evaluate the benefit of this strategy, in pts with DLBCL achieving after salvage CT a 2nd complete remission (CR2), by retrospectively comparing for each pt the progression free survival (PFS) after ASCT with the duration of the previous CR. Adult DLBCL pts with MEDB information available autografted in CR2 between 1990 and 2005 in EBMT centres were included in the analysis. A total of 386 pts (224 males, median age 47 (18–71) years] were evaluated. 294 pts (74%) did not receive RTX prior to ASCT, 67 pts (17%) did receive it at all and in 34 pts (9%) this information is missing. Duration of CR1 was 12 (3 – 142) months [median (range)]; it lasted less than 6 months in 25% of the cases and was longer than 24 months in 25% of the pts. Median time from diagnosis to ASCT was 25 (6–181) months. Peripheral blood was used as the source of hematopoietic stem cells in 311 pts (81%). The BEAM protocol was the conditioning regimen most frequently used (n = 244, 63%) and only 5.5% pts were conditioned with TBI-containing regimens. After a median follow up after ASCT for surviving pts of 42 months, overall survival (OS) was 63% and PFS 48%. 158 pts did relapse after ASCT [median (range), 10 (3–200) months] and 32 pts died from non-relapse mortality. When each patient was taken as her/his own control, PFS after ASCT was longer than CR1 (p 〈 0.001). During the initial phase of the disease, 74% pts experienced 1st relapse in less than 2 years, compared with only 32% of the patients who experienced 2nd relapse 2 years after ASCT. The use of RTX prior to ASCT did not impair the beneficial effects of the autologous procedure in the whole population of pts (RTX no: 66% vs 33%, p 〈 0.001; RTX yes: 73% vs 26%, p = 0.001). 2-years PFS after ASCT was significantly lower in patients with a CR1 〈 12 months (p 〈 0.001). However, in this subgroup of patients PFS after ASCT was significantly longer than CR1 duration when studying each pt as his/her own control (p = 0.001). ASCT can significantly increase PFS in comparison with the duration of CR2 in DLBCL and can change disease course. The use of RTX prior to ASCT does not decrease the beneficial effect of pts autografted in CR2 when compared to their prior CR1 duration. The duration of CR1 remains one of the most important prognostic factors for ASCT outcome.

Description: Background Primary testicular lymphoma (PTL) presents in most cases, histologically, as a diffuse large B-cell lymphoma. PTL has a propensity for metastases to the central nervous system (CNS) cited as 20% at 5 years. Bilateral testicular involvement is seen in 35% of cases. Treatment commonly consists of orchidectomy followed by Rituximab- cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), intrathecal methotrexate (IT-MTX) and prophylactic radiotherapy to the contralateral testis. Administration of systemic high-dose MTX (HD-MTX), at 3 g/m2, has been proposed as an approach to improve CNS parenchymal penetration and may prevent the need for scrotal irradiation. From 2005 within the Anglia Cancer Network, HD-MTX was incorporated into standard treatment for patients with PTL, who were fit enough to receive high dose therapy. Here we report outcomes from the 2 largest lymphoma centres within the network. Method A retrospective review was carried out using medical records of patients with PTL treated with HD-MTX at Cambridge University Hospitals (CUH) and Norfolk and Norwich University Hospital (NNUH), UK, from 2005 onwards. Histological diagnoses were made via orchidectomy or testicular biopsy. Factors reviewed included: age, stage, ECOG performance status, presence of B symptoms and IPI score at diagnosis, treatment regimen, grade 3/4 toxicity and clinical outcome. Stage IV disease was excluded as it cannot be distinguished from a non-testicular primary. Results 10 patients were identified who met the search criteria. 6 were treated at CUH and 4 at NNUH. Median age at diagnosis was 61.5 (49-71). All patients presented with scrotal swelling and 30% had bilateral tumours. ECOG PS was 0 (90%) and 1 (10%). 80% had stage IE disease and 20% stage IIE (paraaortic). Median IPI was 1. Patients were planned to receive 6 cycles of R-CHOP21 with 3-6 cycles IT-MTX with 3 cycles HD-MTX (3 g/m2) administered between or after R-CHOP21. Patients at NNUH only also received radiotherapy at 30 Gy in 15 fractions to the contralateral testis +/- PA nodes if stage IIE disease. One NNUH patient did not receive IT-MTX and one CUH patient only received 2 cycles HD-MTX for logistical reasons. No grade 3 or 4 toxicities were noted. At time of submission with a median follow-up of 4.27 years, only 1 patient has relapsed within the bone marrow. He died of systemic disease but was not shown to have CNS relapse. One patient died of a non-PTL related cause. 8 patients remain in ongoing first remission. No cases of CNS or testicular relapse have been noted in our 10 patients including the 6 patients who did not receive scrotal irradiation. One patient at CUH with bilateral disease was diagnosed on biopsies alone. He underwent unilateral orchidectomy after completing systemic treatment demonstrating a complete response, despite no radiotherapy. He declined a second orchidectomy and remains relapse free at 5.91 years follow-up. Conclusion Treating PTL with HD-MTX, IT-MTX and R-CHOP has shown encouraging clinical outcomes in terms of treatment tolerability and disease-free survival at a median follow-up of 4.27 years. Accepting the small numbers, the absence of CNS relapse with this follow-up suggests prophylactic efficacy of HD-MTX. The finding that disease was eliminated in an in situ testis following treatment is also significant, given the standard practice of contralateral testicular irradiation. These results highlight the need for further prospective research to determine the role of HD-MTX in the management of PTL. Disclosures: No relevant conflicts of interest to declare.

Description: High-dose therapy with allogeneic hematopoietic transplantation (allo-SCT) from matched sibling donors has been shown to induce durable remissions in some patients with relapsed / refractory mantle cell lymphoma (MCL). The aim of this retrospective analysis from the LWP of the EBMT was to investigate the outcome of patients with MCL treated with an unrelated donor allo-SCT (MUD-allo). From January 1994 to July 2005, 66 patients with MCL, 51 males and 15 females, with a median age of 50 years (range, 22 to 68) underwent a MUD-allo and were reported to the EBMT registry. The median time from diagnosis to MUD-allo was 34 months (range, 6–131). Thirty-five patients (53%) had previously failed an autologous procedure (ASCT). Forty-five patients (68%) had sensitive disease (including 22 patients in complete remission) at transplantation, whereas 21 patients (32%) were allografted with refractory disease. Reduced intensity conditioning regimens (RIC) were used in 44 patients (67%). Patients treated with RIC were older, more heavily pre-treated and had more frequently failed an ASCT (46% vs 30%, p = 0.01) than patients treated with a conventional conditioning protocol. Total body irradiation (TBI) was used in 68% of the patients receiving conventional protocols and low-dose TBI in 23% of the RIC patients. Grade II–IV acute graft versus host disease (GVHD) developed in 35% of the cases. The cumulative incidence (CI) of non-relapse mortality (NRM) was of 21% at 6 mo and 27% at 12 mo. The CI of relapse was 35% at 1 year and 45% at 2 years. After a median follow up of 15 months (1–73), 25 patients are alive without progression, with an estimated PFS and OS at 2 years of 28% and 42%, respectively. RIC protocols were not associated with a lower NRM or a better survival. Refractory disease at MUD-allo was an adverse prognostic factor for PFS (RR 1.7; p = 0.006). Patients allografted in sensitive disease presented a better 2-year PFS and OS (34% and 48%, respectively). In conclusion, although follow up is still short, MUD-allo is a feasible procedure in poor prognosis MCL patients, with almost one third of them being alive and progression-free in this series. RIC protocols do not seem to offer any advantage in terms of long-term outcome in relation to conventional conditioning regimens.

Description: Background: Patients (pts) relapsing with CML after allogeneic hematopoietic stem cell transplantation (alloHSCT) may be treated with tyrosine kinase inhibitors (TKI) and/or donor lymphocyte infusions (DLI). As nowadays the majority of CML patients would have received at least imatinib prior to transplantation, we were interested in analizing a) the type of TKI used after alloHSCT, b) the indication for TKI treatment, c) the outcome of this treatment and d) the temporal relationship with DLI if given. Patients and methods: 435 pts received TKI after first allogeneic HSCT for CML for different reasons. Transplants had been performed in first chronic phase (CP1, n=194), accelerated phase (AP, n= 60) or for more advanced disease (blast crisis (BC)/〉 CP1, n=177) from HLA identical siblings (n=231) or unrelated donors (n=204) between 2000 and 2013. TKI given prior to transplant was imatinib (n=268), dasatinib (n=162), nilotinib (n=88), bosutinib (n=4) and ponatinib (n=7). Median age at transplant was 44 (18.5-68) years, 274 pts (63%) were male. TKI post alloHSCT were given between 2000 and 2015. 1st TKI given was either imatinib (n=223), dasatinib (n=131), nilotinib (n=67), bosutinib (n=2) or ponatinib (12). The indications for TKI therapy were the same as for transplantation (n=262), for relapse/progression/persistent disease (n=124), for prophylaxis/pre-emptive (n=32), planned (n=5), others (n=8) and missing (n=4). Results: Median follow-up from start of TKI was 55 (1-171) months. The median time interval from transplant to TKI was 6 (0.2-165) months. It was longer for TKI given for relapse/progression with 15 (1-89) months and shorter for TKI given for prophylaxis/pre-emptive with 1.6 (0.2-43) months. It was longer for imatinib with 11 (0.2-121) months vs 3.8 (0.2-165) months for other TKI. Imatinib as 1st TKI was mainly given for relapse/progression/persistent disease (48%) and the other TKI for the same reason as for transplantation (83%). 103/223 (46%) of pts with imatinib, 99/131 (76%) with dasatinib, 55/67 (82%) with nilotinib and 11/14 (79%) with bosutinib/ponatinib post-transplantation had been treated with imatinib prior to transplantation. In total, 196 (45%) patients received DLI after alloHSCT, of which 63/435 (14.5%) had DLI prior to TKI post-alloHSCT, 19/435 (4.4%) had DLI at the same time of TKI and 114/435 (26%) had DLI post-TKI. Best response after TKI was complete molecular remission in 17.7%, cytogenetic remission in 4.4%, hematological remission in 20.2% and no response/progression/relapse in 57.7% of pts. 50% of pts treated with imatinib had a response (molecular/cytogenetic/hematological) vs 34% with nilotinib, 33% with dasatinib and 33% with bosutinib/ponatinib, p=0.014. OS was 60% (55-65%) at 5 years. It was 66% (60-73%) with imatinib vs 51% (42-60%) with other TKI, p=0.0024. 5 years RFS was 47% (42-53%). It was 53% (46-60%) with imatinib vs 40% (32-48%) with other TKI, p=0.0102. 5 years RI was 25% (21-30%). It was 21% (16-27%) with imatinib vs 31% (24-38%) with other TKI, p=0.0454. 5 years NRM was 27% (23-32%). It was 26% (20-31%) with imatinib vs 29% (22-36%) with other TKI, p=0.365. In multivariate analysis for OS, imatinib vs other TKI post-transplant did not show anymore an effect, HR 1.19 (0.85-1.67), p=0.317. Factors influencing OS were time from diagnosis to transplant, HR 1.01 (1.00-1.01), p=0.009, AP vs CP1, HR 1.80 (1.11-2.91), p=0.017 and BC/〉CP1 vs CP1, HR 2.3 (1.58-3.33), pCP1 vs CP1, HR 2.11 (1.55-2.88), p

Description: INTRODUCTION: Allogeneic stem cell transplantation (allo-SCT) is an important curative strategy in adults with high risk acute myeloid leukemia (AML) and myelodysplasia (MDS). Disease relapse represents the major cause of treatment failure and whilst retrospective analyses have identified that pre-transplant measurable residual disease (MRD) is an important predictor of transplant outcome this has never been examined prospectively. The advent of reduced intensity conditioning (RIC) regimens has substantially increased the number of older adults eligible for allo-SCT but the optimal RIC regimen in high risk AML remains unknown. Registry data have demonstrated improved outcomes using a sequential transplant regimen utilizing cytosine arabinoside (araC)/amsacrine (AMSA) cytoreduction followed by a fludarabine (Flu)/busulfan (Bu) based RIC regimen (FLAMSA-Bu). However, although the FLAMSA-Bu regimen is now widely used in adults with high risk AML and MDS its benefit has not been evaluated in a randomized trial. We report the results of a randomized trial evaluating the FLAMSA-Bu regimen compared with standard RIC regimens which also represents the first prospective evaluation of the impact of pre-transplant MRD levels on transplant outcome. PATIENTS AND METHODS: 244 patients (median age 59 yrs) with high risk AML (n=164) or high risk myelodysplasia (n=80) were randomized 1:1 to a control arm determined by investigator's choice of either Flu/B2/ATG (Flu, Bu 3.2 mg/kg x 2 days, ATG 2.5 mg/kg x 2 days); Flu/Mel/Alemtuzumab (A) (Flu, Mel 140 mg/m2, A 50 mg) or Flu/Bu2/A (Flu, Bu 3.2 mg/kg x 2 days, A 50 mg) versus an experimental arm of FLAMSA-Bu (Flu, araC 2g/m2 x 4 days, AMSA 100mg/m2 x 4 days, Bu -total dose 11.2 mg/kg). Patients over the age of 60 received an adjusted FLAMSA-Bu regimen utilising a reduced dose of araC (1mg/m2 x 4 days) and a total Bu dose of 6.4 mg/kg. Patients were transplanted using either an HLA identical sibling (n=49) or matched (10/10 or 9/10) unrelated donor (n=195). All patients received cyclosporine GVHD prophylaxis. 155 patients with AML were in CR1 or CR2 at the time of transplant and 9 had primary refractory disease. MRD was monitored by flow cytometry (applying different-from-normal analysis when no diagnostic/relapse leukemic aberrant immunophenotype was available). Pre-transplant MRD levels were measured up to four weeks prior to transplantation in 201 patients (MRD positive = 80 (40%), MRD negative = 94 (47%), inadequate sample = 27 (13%)). MRD results were not reported to clinicians. The primary outcome was overall survival. RESULTS: Baseline characteristics including CR1/CR2 status, adverse cytogenetics and MRD levels were similar between regimens. Median follow up was 35 months. Transplant outcomes were comparable between patients allografted in the control and FLAMSA-Bu arms. 2 yr overall survival (OS) and cumulative incidence of relapse (CIR) were 61% and 30% respectively in the control arm vs 62% and 26% for the FLAMSA-Bu arm. Transplant related mortality at 100 days was 3.0% in patients allografted using the control regimen vs 14% in patients allografted using the FLAMSA-Bu regimen and 17% vs 21% at 1 year. In the study cohort pre-transplant MRD positivity was associated with both an increased CIR compared to patients testing MRD negative (2 yr CIR 42% vs 19%, p=0.009) and decreased OS (2 yr OS 52% vs 71%, p=0.048). The FLAMSA-Bu regimen failed to improve OS or reduce CIR in either MRD positive or MRD negative patients. CONCLUSIONS: This trial, the largest randomized trial of RIC regimens in AML to date, did not detect any benefit of intensification of the conditioning regimen in adults with high risk AML or MDS. Specifically, the FLAMSA-Bu regimen was not associated with improved transplant outcome in patients who were MRD positive pre-transplant. These data include the first demonstration in a prospective analysis that the presence of pre-transplant MRD measured in real time is associated with reduced OS consequent upon an increased risk of disease relapse. Further randomized studies of novel conditioning regimens in adult AML, crucially with integrated MRD studies, are now required but these results support exploration of alternative strategies, such as pre or post-transplant pharmacological intervention, as the most promising strategy to reduce the risk of disease relapse post allograft. Disclosures Russell: Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Freeman:Jazz Pharmaceuticals: Speakers Bureau. OffLabel Disclosure: We report data using the combination of fludarabine, busulphan, amsacrine and cytosine arabinsoide as a conditioning regimen in patients allografted for high risk acute myeloid leukemia

Description: In vivo alemtuzumab reduces the risk of graft-versus-host disease (GVHD) and nonrelapse mortality after reduced intensity allogeneic transplantation. However, it also delays immune reconstitution, leading to frequent infections and potential loss of graft-versus-tumor responses. Here, we tested the feasibility of alemtuzumab dose deescalation in the context of fludarabine-melphalan conditioning and human leukocyte antigen (HLA)–identical sibling transplantation. Alemtuzumab was given 1-2 days before graft infusion, and dose reduced from 60 mg to 20 mg in 4 sequential cohorts (total n = 106). Pharmacokinetic studies were fitted to a linear, 2-compartment model in which dose reduction led to incomplete saturation of CD52 binding sites and greater antibody clearance. Increased elimination was particularly evident in the 20-mg group in patients who had CD52-expressing tumors at time of transplantation. The 20-mg dose was also associated with greater risk of severe GVHD (acute grade III-IV or chronic extensive) compared with 〉 20 mg (hazard ratio, 6.7; 95% CI, 2.5-18.3). In contrast, dose reduction to 30 mg on day −1 was associated with equivalent clinical outcomes to higher doses but better lymphocyte recovery at 12 months. In conclusion, alemtuzumab dose reduction to 30 mg is safe in the context of reduced intensity conditioning and HLA-identical sibling transplantation. This trial was registered at http://www.ncrn.org.uk as UKCRN study 1415.