ALBERT

Description: Autologous stem cell transplantation (ASCT) remains the standard consolidation therapy for patients with multiple myeloma (MM) and chemosensitive relapsed lymphoma (r-Ly). Peripheral blood as a source of stem cells (PBSC) has largely replaced marrow and has the advantage of improved engraftment rates. PBSC are routinely collected following administration of chemotherapy in combination with GCSF. However, the resultant pancytopenia poses a significant risk to patients and additional chemotherapy prior to ASCT may lead to increased end organ damage potentially precluding future therapies (including ASCT). Novel agents can achieve PBSC mobilisation without the use of cytotoxics. In the advent of such drugs, we reviewed the efficacy of, and complications experienced by patients during PBSC mobilisation. We also analysed the cost implications of adverse events. Of 151 consecutive attempts, 13.2% of patients failed to reach our criteria in order to attempt pheresis (1 × 104 CD34 cells/ml). Of those achieving target and undergoing pheresis, 6% did not achieve an adequate cell dose for future ASCT (2 × 106CD34+cells/kg) giving an overall failure rate of 19.2%. Furthermore 17.9% failed to harvest our ideal of 4 × 106/kg (permitting 〉1 ASCT procedure). Factors contributing to failure in achieving target CD34+ve PB count on univariate analysis were; 〉2 lines of previous chemotherapy and occurrence of neutropenic sepsis (NS (p=0.002, and 0.005 respectively). These factors remained significant on multivariate analysis (RR: 4.4 and 6.2). These same factors also affected CD34+ cell yield on both univariate and multivariate analysis (RR: 3.3 and 4.6). No differences were seen between MM and r-Ly. Overall, the complication rate was 34.4%, with 24.1% of patients suffering NS requiring admission. The mortality rate was 1.3% (NS and intra-cranial bleed). Of those developing NS, only 52% eventually harvested sufficient cells, but with a median delay of 3 days. The median cost of PBSC collection was $17,381.46 ($1,978.97–$39,355.73). NS significantly increased the cost of mobilisation at a median cost of $25,532.95 vs $16,4921) (p=

Description: Background: Allogeneic SCT is considered standard treatment for patients with advanced phase CML (accelerated phase, blast crisis), de novo Ph+ ALL, or patients in chronic phase (CP) resistant or intolerant to at least 2 tyrosine kinase inhibitors (TKI). Ponatinib is FDA and EMA approved for the treatment of CML or Ph+ ALL in patients with the BCR-ABL1 T315I mutation or for whom no other TKI therapy is indicated. In patients harboring the T315I mutation, ponatinib currently represents a suitable alternative treatment option to allogeneic SCT. However, differences in outcomes between patients treated with ponatinib and allogeneic SCT have not been analyzed. Objective: To compare overall survival (OS) among CML and Ph+ ALL patients with the BCR-ABL1 T315I mutation treated with ponatinib (in PACE) versus allogeneic SCT (in the EBMT database). Methods: Data from a Phase II trial of ponatinib (PACE trial; Cortes et al., New Engl J Med 2013; NCT01207440) and European Bone Marrow Transplant (EBMT) registry were pooled to conduct an indirect comparison of ponatinib with allogeneic SCT. Both ponatinib and allogeneic SCT cohorts comprised patients with the T315I mutation age 18 years or older in any phase of CML or with Ph+ ALL. All patients harbored the T315I mutation detected by Sanger sequencing, DHPLC, PCR-RFLP, or other equivalent tests. Allogeneic SCT patients in their second CP phase were excluded, and no patients in the EBMT database were treated with ponatinib prior to receiving allogeneic SCT. The date of intervention (ponatinib or SCT) served as the index date. Baseline demographic and clinical characteristics were compared between the two intervention groups. OS was compared between the two groups using adjusted Kaplan-Meier (KM) survival curves and multivariate Cox proportional hazards models; all comparisons were adjusted for age (as a continuous variable), gender, geographic region (Europe, Asia, and Australia vs. North America), time from CML diagnosis to intervention, and CML phase or Ph+ ALL at intervention to control confounding by these variables. Results were presented overall and stratified by phase of CML or Ph+ ALL. Results: A total of 184 (128 ponatinib, 56 allogeneic SCT) patients were included in the analysis: 90 were in CP-CML, 26 were in accelerated phase (AP-CML), 41 were in blast phase (BP-CML), and 27 had Ph+ ALL. On average, ponatinib patients were older than allogeneic SCT patients on the date of intervention (median age 53 vs. 45 years, p=0.006). In addition, a larger proportion of patients in the ponatinib group were from North America than in the allogeneic SCT group (43.8% vs. 26.8%, p=0.030). Median time from diagnosis to intervention was longer for patients treated with ponatinib compared with those treated with allogeneic SCT in CP-CML (58 vs. 32 months, p=0.029), but not significantly different in AP-CML (80 vs. 49 months, p=0.075) nor Ph+ ALL (17 vs. 10 months, p=0.212). This period was nominally shorter for the ponatinib cohort in BP-CML (26 vs. 43 months, p=0.340). Over 93% of patients in both treatment cohorts in all disease phases reported previous use of imatinib. Adjusted median OS was significantly longer in CP-CML patients treated with ponatinib as opposed to allogeneic SCT patients (KM median: not reached [NR] vs. 103.3 months, p=0.013), with a hazard ratio (HR) of 0.37 (95% CI: 0.16, 0.84, p=0.017). Median OS was not significantly different between the two treatment groups in patients with AP-CML (NR vs. 55.6 months, p=0.889; HR=0.90 [95% CI: 0.20, 4.10, p=0.889]). However, among patients with BP-CML, ponatinib was associated with significantly shorter OS compared with allogeneic SCT: median 7.0 vs. 10.5 months (p=0.026), HR=2.29 (95% CI: 1.08, 4.82, p=0.030). Ph+ ALL patients treated with ponatinib had nominally shorter median OS than allogeneic SCT (6.7 vs. 32.4 months, p=0.119; HR=2.77 [95% CI: 0.73, 10.56, p=0.136]). See Figures 1a-1d for adjusted KM survival curves. Conclusion: AllogeneicSCT remains a potential curative therapy for patients with BP-CML. However, ponatinib was associated with significantly longer OS than allogeneic SCT in patients with CP-CML that harbor the T315I mutation and could represent a promising therapeutic alternative in this setting, although follow-up remains short to date. OS was similar between intervention groups in AP-CML and longer for allogeneic SCT patients in BP-CML and Ph+ ALL. Disclosures Nicolini: Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Basak:MSD: Consultancy, Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Pierre-Fabre: Honoraria. Kim:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:BMS: Consultancy, Speakers Bureau; Novartis: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau. Apperley:ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Ariad: Consultancy; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Chuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chiltern International: Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; ROCHE: Consultancy; BMS: Consultancy, Speakers Bureau; AMGEN: Consultancy. DerSarkissian:ARIAD: Research Funding. Kageleiry:ARIAD: Research Funding. Yang:ARIAD: Employment. Huang:ARIAD: Employment, Equity Ownership. McGarry:ARIAD: Employment, Equity Ownership. Cortes:Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Description: Donor lymphocyte infusions (DLI) have radically changed the prognosis of patients relapsing after allogeneic hematopoietic stem cell transplant (SCT) for chronic myeloid leukemia (CML). Major obstacles to success with DLI are represented by leukemia resistance and by secondary GvHD (GvHD2). The best result of is when a patient treated with DLI achieve a durable molecular remission without experiencing GvHD2. It is unclear which factors may predict for such a favourable outcome when CML patients are treated with DLI. We retrospectively identified 500 patients (59% males, median age 39 years, range 4–64), treated with DLI for CML relapse (81 molecular [16%], 150 cytogenetic [30%], 211 hematological chronic [42%], and 58 hematological accelerated [12%]) at 68 EBMT centers before 2004 with adequate information collected on disease response, GvHD2 and survival after DLI. Donor was an HLA-identical sibling in 73%, unrelated in 27%. DLI started with a cell dose 1997), showed that chronic GvHD after transplant and prior to relapse (hazard ratio [HR]: 1.5, 95CI: 1.2–1.9, p

Description: We analyzed factors having an impact on response to treatment and survival in 78 consecutive patients with chronic myeloid leukemia (CML) in blastic transformation (BT) referred to the Hammersmith Hospital from January 1995 to December 2000. BT was defined as the presence of at least 30% blasts in blood or marrow or extramedullary blastic deposits. Immunophenotyping of blasts showed 57 myeloid, 19 lymphoid, and 2 biphenotypic. The median age of the patients was 39.1 years (range, 11.3-73.4 years), with 55 males and 23 females. The median survival for all patients after onset of BT was 8.2 months (95% CI, 6.4-10). Patients in lymphoid BT survived longer than those in myeloid BT (median, 11.2 months versus 6.9 months, P = .052). Initial treatment varied; 41 patients received cytotoxic drugs, 8 underwent allogeneic or autologous transplantation procedures, 21 received STI571 (imatinib mesylate, Gleevec), 1 received radiotherapy, and 7 received no therapy. Of the 25 (32%) patients who achieved a “second chronic phase” with first therapy, 6 of 21 (29%) were treated with STI571 and 19 of 50 (38%) were treated with chemotherapy, transplantation, or radiotherapy. Patients who achieved a second chronic phase survived longer than those who did not (median time from onset of BT 12.0 months versus 6.3 months, P = .0004). In multivariate analysis the finding of more than 50% blast cells in the blood and the presence of cytogenetic progression were independent adverse prognostic variables for survival. We conclude that survival after onset of BT has improved in recent years but is still unsatisfactory. We speculate that the combined use of STI571 with cytotoxic drugs may offer additional benefit.

Description: Non-HLA polymorphisms (NHP) influence risk of GVHD and outcome of allogeneic hematopoietic stem cell transplants (HSCT) however their influence on GvHD vs GvL remains to be defined. A cohort of 291 CML HLA matched sibling transplants with known clinical risk factors; eg stage of disease, gender mismatch (female donor/male recipient), patient age and time from diagnosis to transplant as defined by the EBMT risk score, were typed via SNPs or microsatellites for cytokines (IL-1Ra, IL-4, IL-6, IL-10, IFNγ, TNFα, TNFR 11), steroid hormone receptors (VDR and ERα) and NOD2/CARD15 mutations. TNFRII-196 allele R; IL-10 ATC/ACC; IL-1 Ra (allele 2) and IL-4T were significantly associated with survival using univariate analysis. Two clinical Cox proportional hazards models were generated for the statistical analysis and used as a basis for further development: (i) using the EBMT risk score as a single variable on an ordinal scale or (ii) using the individual clinical factors of the EBMT risk score as categorical variables. After step-wise variable selection using the significant genetic factors as candidates, the resulting multivariate models indicated that absence of TNFRII-196 R, i.e. down regulation of TNF in the recipient, absence of IL-10 ATC/ACC, i.e. intermediate IL-10 production in the donor and presence of IL-1Ra (allele 2) i.e. down regulation of IL-1 in the donor were associated with poor outcome. The addition of the genetic variables significantly improved the preferred model containing the EBMT risk score as a single variable. The Goodness of Fit of the models was assessed by Kaplan-Meier curves showing clinically relevant differences between good, intermediate and poor prognostic groups. The worst prognostic scores included the absence of ATA/ACC in the donor, evidenced by a steep change in survival probability. Relapse was associated with clinical factors; absence of female to male transplants; absence of bone marrow transplants and presence of T cell depletion but no significant association was found with genetic factors. This study suggests that distinct high risk patterns of NHP of patients and donors can be defined, which influences survival due to factors associated with an increased risk of GvHD without the potential benefit of increased GvL response. Data add to the clinical factors (eg age, sex, multiparity of the donor) where an unrelated donor might be the preferred choice compared to a high risk sibling donor.

Description: Abstract 991 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: 〉10% of PCs in BM, serum MC 〉30g/L, 〉95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both 〉PC 10% and MC 〉30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly). The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria). According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%. After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p

Description: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is no longer the first treatment option for patients with chronic myelogenous leukemia (CML) but there is a considerable debate about its use as a second line therapy. When used in this indication the second-generation tyrosine kinase inhibitors (2G-TKI) induce complete cytogenetic responses (CCyR) in 40–50% of patients in chronic phase but those without CCyR are unlikely to benefit in long term. It is therefore important to identify groups of patients with a good outcome after transplantation so that this may be offered as second line therapy where appropriate. The outcome of allo-SCT has improved over time so we restricted our analysis to the most recent 8 years to coincide with the introduction of imatinib into clinical practice. 131 patients received myeloablative transplants from January 2000 till December 2007. 67 patients were transplanted in chronic phase (14 in second and 2 in third chronic phase), 46 in accelerated phase and 2 in blastic phase. Forty-nine patients received imatinib at some point prior to transplantation and 30 of these experienced failure of imatinib therapy (as defined by European LeukemiaNet criteria). Conditioning consisted of cyclophosphamide and total body irradiation for 51 recipients of sibling stem cells. In addition in vivo T cell depletion with anti CD52 antibody (Campath 1H) was used for 80 unrelated donor transplants. The median age of the patients was 33.4 (15 to 56) years and the median disease duration at transplant was 13 (2 to 105) months. The probability of overall survival (OS) at 3 and 5 years was 64.8% and 62.6% respectively. We confirmed the prognostic value of the EBMT risk assessment score (Gratwohl) and pretransplant level of the C-reactive protein (CRP) and developed a combined additive pretransplant scoring system based on these predictive factors (EBMT risk assessment score plus 0 for CRP 10 mg/L). This identified 5 prognostic groups (Figure 1) with 3yr probabilities of survival of 92.6% (N= 27, score 0–1), 86.2% (N=29, score 2), 58.2% (N=29, score 3), 47.5% (N=20, score 4) and 30.8% (N=26, score 5 or more). The patients who failed imatinib (N=30) had significantly higher prognostic scores on the above described pre-transplant scoring system compared to the rest of patients transplanted (p=0.001). However, in a multivariate analysis adjusted for prognostic scores, their OS was significantly better (p=0.032). The OS in the best prognostic group is comparable with that of unselected patients treated with imatinib and it is possible that their long-term survival might be better. Allogeneic transplantation is unlikely to be preferred as the first line therapy even in selected patients due to its higher early mortality but our data support its use as second line therapy in patients in chronic phase who failed imatinib and have poor pre-2G-TKI predictive factors for CCyR as determined previously at our institution (namely Sokal risk score at diagnosis, the best cytogenetic response obtained on imatinib, G-CSF requirement during imatinib therapy and time from detection of imatinib failure to onset of 2G-TKI therapy) but achieved good score on the pre-transplant scoring system. It should also be used for those whose disease is more advanced where the 2G-TKI do not offer durable remissions. Figure 1 Figure 1.

Description: Background: Despite adequate treatment and favorable initial outcome, the risk of recurrence of a previous invasive fungal infection (IFI) or acquisition of a new one is a major obstacle to the success of stem cell transplantation (SCT). The rate of IFI relapse is estimated to be 30 to 50%. Secondary prophylaxis could increase survival and reduce the burden of fungal infections to these patients. Methods: A prospective open multicenter trial was performed to evaluate the efficacy of voriconazole (VORI) (4mg/kg/12h IV or 200mg/12h oral) as secondary prophylaxis in allogeneic SCT patients with previous proven or probable IFI (2002 EORTC/MSG consensus criteria). Adult patients (Age 〉 18 y) were eligible if the prior IFI had occurred within the 12 months prior to SCT. Exclusion criteria were prior resistance to VORI, prior history of zygomycosis, or active IFI at time of transplant. VORI was started within 3 days before transplant and planned for 100 days. Prophylaxis could be prolonged up to 150 days in case of persistent graft-versus-host disease (GVHD) and ongoing immunosuppression on day 100. All patients were followed until 12 months post-transplant, or until death, whichever occurred first. The primary endpoint was the rate of proven and probable IFI between the start of VORI prophylaxis and the 12 month follow-up. Diagnosis of prior IFI, diagnosis of IFI occurring during the study, and cause of deaths, were assessed by a Data Review Committee including an independent radiologist. Results: 45 patients from 17 EBMT centers were included from Feb 2005 to March 2007. The mean age was 48 y (22–72). Forty-one had acute leukemia, and 24 were in first complete remission. Previous IFI included proven (n= 6) or probable (n=26) aspergillosis, proven candidiasis (n=5), and others (n=8). The mean time from diagnosis of the previous IFI to SCT was 151 days. Twenty four patients were transplanted from a family donor (HLA-id: 18; mismatched: 5; twin: 1), and 21 from an unrelated donor. The graft was bone marrow (n=6), peripheral blood stem cells (n=38) or cord blood (n=1). The conditioning regimen was myeloablative in 27 and non myeloablative in 18 patients. The median follow-up was 360 days (range 5–469). Twenty-six (58%) patients experienced at least one episode of GVHD. Three cases of IFI were recorded after transplant: one C. albicans candidemia, one S prolificans fungemia and one zygomycosis, at day 3, 16, and 66 after transplant, respectively (incidence: 7%). Two of these 3 IFI were relapses of a previous IFI. The median duration of the VORI prophylaxis was 94 days (5–180). Eleven patients (24%) died between 96 and 326 days post-transplant (median: 136 days) from scedosporiosis (n=1), leukemia relapse (n=4), respiratory failure or pneumopathy of unknown origin (n=3), GVHD (2), or sepsis (n=1). Conclusion: Voriconazole appears to be an efficient drug for secondary prophylaxis of proven and probable IFI after allogeneic SCT, with few adverse events. Considering an expected rate of IFI occurrence or recurrence after transplant of around 30%, the observed rate of 7%, and only one death from IFI in this high-risk adult population are promising.