Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

Unrelated or haploidentical allogeneic hematopoietic cell transplantation in second complete remission for acute myeloid leukemia-Improved outcomes over time: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party study.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only cure for acute myeloid leukemia (AML) in second complete remission (CR2). Patients lacking a matched sibling donor (MSD) receive transplants from matched unrelated donors (MUDs), mismatched unrelated donors (MMUDs), haploidentical (haplo) donors, or cord blood. METHODS: This is a retrospective, registry-based European Society for Blood and Marrow Transplantation study that investigates changes in patient- and transplant-related characteristics and posttransplant outcomes over time. RESULTS: We identified 3955 adult patients (46.7% female; median age, 52 years [range, 18-78 years]) with AML in CR2 first transplanted between 2005 and 2019 from a MUD 10/10 (61.4%), MMUD 9/10 (21.9%), or haplo donor (16.7%) and followed for 3.7 years. A total of 725 patients were transplanted between 2005 and 2009, 1600 between 2010 and 2014, and 1630 between 2015 and 2019. Over the three time periods, there was a significant increase in patient age (from 48.7 to 53.5 years; p < .001), use of a haplo donor (from 4.6% to 26.4%; p < .001), and use of posttransplant cyclophosphamide (from 0.4% to 29%; p < .001). There was a significant decrease in total body irradiation and in vivo T-cell depletion. In multivariate analysis, transplants performed more recently had better outcomes. Leukemia-free survival (hazard ratio [HR], 0.79; p = .002) and overall survival (HR, 0.73; p < .001) increased over time. Similarly, nonrelapse mortality (HR, 0.64; p < .001) decreased over time. We also observed better graft-vs-host disease (GVHD) rates (acute GVHD II-IV: HR, 0.78; p = .03; GVHD-free, relapse-free survival: HR, 0.69; p < .001). CONCLUSIONS: Even in the absence of an MSD, outcomes of allo-HCT in CR2 for AML have significantly improved over time, with most favorable outcomes achieved with a MUD.

Prognostic impact of early-versus-late responses to different induction regimens in patients with myeloma undergoing autologous hematopoietic cell transplantation: Results from the CALM study by the CMWP of the EBMT.

BACKGROUND: In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. METHOD: We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5 months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor). RESULTS: The length of induction treatment required to achieve a Good response did not affect PFS (P = .65) or OS (P = .61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (P = .31), and median OS 81.7, 92.7, and 77.4 months, respectively (P = .83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, P-value = .02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post-transplant. CONCLUSION: The kinetics of response did not affect outcomes.

Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: A Retrospective Study by the EBMT Chronic Malignancies Working Party.

The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry-based study of adult patients allografted for BC CML, focusing on patients with active disease at transplant and pretransplant prognostic factors. One hundred seventy patients allografted for BC CML after tyrosine kinase inhibitor pretreatment between 2004 and 2016 were analyzed. Before transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (hazrd ratio, 1.87; P = .010) and shorter leukemia-free survival (LFS; hazard ratio, 1.69; P = .017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended toward improved overall survival. In summary, survival of patients allografted for BC CML was strongly dependent on pretransplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplant was associated with prolonged LFS in our study.

Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates.

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation.

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.

BACKGROUND: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability. METHODS: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented. FINDINGS: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia). INTERPRETATION: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers. FUNDING: Blood Cancer UK and Incyte.

Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p = 0.02). Incidence of acute GVHD was similar, 38% and 36% (p = 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p = 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p = 0.87), 25% vs. 30% (p = 0.4), 52% vs. 46% (p = 0.3), 59% vs. 50% (p = 0.2), and 44% vs. 41% (p = 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p = 0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p = 0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p = 0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p = 0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p = 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar.

Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.

Total body irradiation + fludarabine compared to busulfan + fludarabine as "reduced-toxicity conditioning" for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT.

The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two "reduced-toxicity" regimens: intravenous busulfan at a total dose of 9.6 mg/kg (3 days) + fludarabine (Bu3/Flu) and total body irradiation at a dose of 8 Gy + fludarabine (TBI8Gy/Flu). In the entire study cohort (n = 518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p = 0.051), 59.5% vs. 65% (p = 0.15), 30% vs. 20% (p = 0.01), and 10% vs. 14% (p = 0.18), respectively. In multivariate model for patients <50 years old, TBI8Gy/Flu was associated with improved LFS (hazard ratio (HR) = 0.5, p = 0.04), OS (HR = 0.31, p = 0.004), and survival free from both graft-versus-host disease and relapse (HR = 0.55, p = 0.03), as well as tendency to reduced risk of relapse (HR = 0.53, p = 0.08). Among patients aged 50 years or older the use of TBI8Gy/Flu was associated with increased incidence of NRM (HR = 3.9, p = 0.0009), with no significant impact on other outcome measures. We conclude that the use of TBI8Gy/Flu as "reduced-toxicity" regimen may be advised in younger patients with AML referred for allo-HCT.

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80%: A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT).

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS score <80% (p < 0.001). In the subgroup of patients with a KPS score =80%, a reduced-intensity conditioning (RIC) regimen was associated with an increased risk of relapse (p = 0.002) and lower GRFS (p < 0.001) compared to myeloablative conditioning (MAC). Differently, in patients with a KPS score <80%, a RIC regimen resulted in lower NRM (p < 0.001), whereas relapse incidence did not differ, thus leading to an improved GRFS (p = 0.008) as compared to MAC. A transplant from a matched sibling donor (MSD) was associated with a reduced incidence of grade III-IV acute GVHD (p < 0.01) and NRM (p < 0.01) in comparison to other donor types. In conclusion, allo-SCT appears feasible in AML patients with a jeopardized KPS score. Survival is significantly affected by the conditioning intensity, which should be adjusted according to the severity of KPS impairment.

Impact of critical care reconfiguration and track-and-trigger outreach team intervention on outcomes of haematology patients requiring intensive care admission.

Patients with haematological disorders have previously been considered to have poor outcomes following admission to intensive care units. Although a number of haematology centres from outside the UK have now demonstrated improved outcomes, the continuing perception of poor outcomes in this patient group continues to adversely affect their chances of being admitted to some intensive care units (ICUs). Over the past 10 years, there have been many advances within the disciplines of both haematology and intensive care medicine. This study was done to assess outcomes and the impact of an early warning scoring system (EWS) and early involvement of ICU outreach teams. One hundred five haematology patients (haematopoietic stem cell transplant (HSCT) or non-HSCT) had 114 admissions to ICU between April 2006 and August 2008 which coincided with hospital-wide implementation of EWS. The survival to ICU discharge was 56 (53%). Thirty-three (33%) patients were alive at 6 months giving a 1-year survival of 31%. Of the 39 HSCT patients, nine were post-autologous and 30 post-allogeneic transplant. The survival to ICU discharge was 22 (56%) with 14 (36%) patients alive at 6 months. One year survival was 36%. Prior to the introduction of EWS and critical care outreach team (2004), survival to ICU discharge was 44% which has increased to 53% (2006-2008). This is despite an increase in mechanical ventilation in 2006-2008 (50%) as compared to 2004 (32%).The improvement in ICU survivorship was even more prominent in HSCT patients (37% in 2004 versus 56% in 2006-2008). There was a trend towards decreasing Acute Physiology and Chronic Health Evaluation scores with time, suggesting appropriate patients being identified earlier and having timely escalation of their treatment.

Presence of donor-encoded centromeric KIR B content increases the risk of infectious mortality in recipients of myeloablative, T-cell deplete, HLA-matched HCT to treat AML.

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.

BACKGROUND: Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. METHODS: We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. FINDINGS: Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib. INTERPRETATION: TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted. FUNDING: Newcastle University and Bloodwise.

The impact of chimerism patterns and predonor leukocyte infusion lymphopenia on survival following T cell-depleted reduced intensity conditioned transplants.

Donor leukocyte infusions (DLI) are frequently required following reduced intensity conditioned (RIC) allografts to convert mixed chimerism (MC) to full donor chimerism (FDC). The rationale is to break tolerance and maximize the graft-versus-leukemia responses. We analyzed the impact of chimerism in 125 recipients of RIC (Alemtuzumab containing) transplants. Four patterns of chimerism were seen: (1) always 100% donor chimerism (54%), (2) persisting MC (22%), (3) MC with subsequent development of FDC (18%), (4) lost donor chimerism (6%). Forty-five (36%) patients received DLI. Chimerism patterns and pre-DLI lymphocyte counts (pDLI[Ly]) were significantly associated with DLI responsiveness. Complete disease responses were seen in 6 of 17 (35%) group A patients, 9 of 10 (90%) group C patients, and 0 of 6 group B patients (P = .027), supporting reports that chimerism response is a surrogate marker for disease response. In those with MC, pDLI(Ly) were significantly lower in DLI responsive than nonresponsive patients (P = .044). At 2 years, group C patients had a significant survival advantage (P = .009) compared to all other groups. In conclusion, the chimerism pattern was the best indicator of improved survival in this cohort (ie, MC later converting to FDC). In those with MC, response to DLI therapy was associated with a low lymphocyte count pre-DLI.

Ifosphamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilisation regimen for transplant-eligible patients with non-Hodgkin lymphoma and Hodgkin disease.

A total of 143 patients with relapsed (n = 90), primary refractory (n = 32) and first line chemotherapy responsive (n = 21) non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were treated with IVE (ifosphamide, etoposide and epirubicin) chemotherapy with the intent to proceed to high-dose therapy with either autologous or allogeneic transplantation, following peripheral blood stem cell mobilisation. A major response (complete/partial response) to IVE was seen in 115 patients (80.4%) with 5-year overall survival (OS) and event free survival (EFS) of 53% and 43%, respectively. Subgroup analysis showed overall response rates of 93.1% for HD with a 5-year OS and EFS of 62% and 52% respectively, while NHL showed response rates of 78.0% with 5-year OS and EFS of 50% and 39% respectively. The median number of CD34 +ve cells mobilised following IVE was 7.86 x 10(6) (range 1.72-42.91 x 10(6)), with 60% mobilising >2 x 10(6)/kg in a single collection. Grade IV neutropenia was seen in 79.6% patients and 77/270 cycles required intravenous antibiotic treatment. We conclude that IVE has a high response rate across a range of refractory and relapsed lymphoma with acceptable toxicity and excellent PBSC mobilising characteristics.

Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia.

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.

Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission.

Imatinib mesylate (IM, STI 571, Glivec) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT-PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [rHu-G-CSF; 10 micro g/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11.5/ microl (range 0-108/ microl), and 43/58 (74%) patients underwent a median of two (range 1-3) apheresis procedures. A median dose of 2.1 x 10(6)/kg CD34+ cells (range 0.1-6.5 x 10(6)/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR-ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 x 10(6)/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph- CD34+ cells from IM-treated patients in CCR is possible using rHu-G-CSF alone.