Achieved MRD Negativity Research Articles

PF604 THE AUSTRALASIAN LEUKAEMIA AND LYMPHOMA (ALLG) GROUP MM17 TRIAL: RESPONSE ADAPTIVE SALVAGE WITH CARFILZOMIB‐THALIDOMIDE‐DEXAMETHASONE FOR MULTIPLE MYELOMA PATIENTS FAILING FRONT‐LINE BORTEZOMIB

Background:Over 90% of transplant eligible newly diagnosed multiple myeloma (TE‐NDMM) patients (pts) in Australia are induced with bortezomib (V)‐ cyclophosphamide‐dexamethasone. Of these, 15% demonstrate either a sub‐optimal response (<partial response [PR]) (SOR) or primary refractoriness (1REF). These pts experience short progression free (PFS) and overall survival (OS), thus representing an area of ongoing unmet medical need.Aims:The ALLG MM17 trial was designed to evaluate an early response adaptive switch to carfilzomib‐thalidomide‐dexamethasone (KTd) and to define the mutational spectrum of disease in TE‐ NDMM patients failing V‐induction.Methods:Pts were either SOR (defined as 2on D1, 2, 8, 9, 15 and 16 of each 28‐day cycle (27 mg/m2D1 and 2 of cycle 1); T 100 mg D1–28; and, d 40 mg on D1, 8, 15, and 22 of each cycle. Pts were planned to receive KTd x 4 cycles then undergo re‐staging. Those achieving a stringent complete response (sCR) (morphologically normal bone marrow [BM], IF negativity, normalisation of the involved light chain isotype) proceeded to a MEL200 ASCT. Those withResults:Fifty pts were recruited between 9/2016 and 4/2018. Data cut‐off date was November 7, 2018 with the reverse‐Kaplan‐Meier estimate of the median potential follow‐up for survival being 14.8 months (95% CI: 9.7 – 17.8 months). Median age was 50 years (36–71) with 72% males. Median time from initial therapy to study entry was 4 months with disease status at entry of SOR in 26 (66%) (<MR n = 13, <PR n = 13) and 1REF in 13 (33%). EMC92 stratification demonstrated high‐risk disease in 48%. The tumour suppressor CDC27 (Anaphase‐promoting complex E3 ubiquitin ligase) was the most commonly mutated gene at study entry with a high proportion of patients also manifesting potentially targetable lesions – ATR, ATM, PIK3CA, FGFR3 and KRAS. The median number of pre‐ASCT KTd cycles was 6 (range 1 to 6). ORR was 78% (95% CI: 64–87%)∗‐ sCR 12%, CR 6%, VGPR 38% and PR 22%. On an intention‐to‐treat basis 32% of pts were MRD neg pre‐ASCT, 40% at day 100 post‐ASCT and 51% post KTd consolidation. Ten pts have progressed, 7 with highly aggressive extra‐medullary disease. No patient that achieved MRD negativity has progressed. Neither median PFS nor OS have been reached.Summary/Conclusion:KTd produces high response rates and MRD negativity in TE‐NDMM patients failing V‐based induction. TAS revealed a novel mutational spectrum consistent with treatment selection of V‐resistant sub‐clones likely present at diagnosis.

PB1726 DOUBLE FLUDARABINE‐BASED INDUCTION AND INFECTIVE RISK: THE BOLOGNA EXPERIENCE.

Background:“3+7” represents the current standard of care for acute myeloid leukemia (AML). Fludarabine‐based regimens have limited application due to the absence of survival benefit and prolonged hematological toxicity after 2nd cycle. Infections in neutropenic patients represent an important cause of mortality and morbidity.Aims:To analyze the infective risk associated with intensive chemotherapy based on double‐FLAI induction.Methods:We retrospectively collected data of 40 consecutive adult patients with newly diagnosed AML treated with FLAI‐5 induction therapy (Fludarabine IV 25 mg/sqm/die days 1‐5, Cytarabine IV 2000 mg/sqm/die days 1‐5 and Idarubicin 10 mg/sqm/die on days 1, 3 and 5). Patients in complete remission (CR) proceeded to second FLAI‐5 followed by allogeneic transplant or chemotherapy consolidation. The incidence and type of infective events were collected in 36/40 patients. Patients were compared with a historical court of 39 patients treated with non‐fludarabine based induction. MRD was assessed by qRT‐PCR or WT1 gene expression. Data were harmonized using RedCap custom eCRFs.Results:Forty patients received FLAI‐5 from August 2015 to December 2018. Median age at diagnosis was 53 years (range 19‐66). According to NCCN‐2016 stratification criteria 12/40 (30%) patients were favorable, 10/40 (25%) intermediate and 17/40 (42.5%) high risk; one patient wasn’t evaluable. Thirty‐five patients (87.5%) achieved a CR after induction, 4 (10%) patients were refractory and 1 patient (2.5%) died during induction. Twenty‐nine of 40 patients were evaluable for MRD analysis and 15/29 (52%) patients achieved MRD negativity. Twenty‐two of the 35 patients in CR proceeded to 2nd FLAI‐5 chemotherapy regimen.At induction, patients recovered from neutropenia (ANC> 500 x 109/L) after 21.5 days (range 13‐32) from the end of chemotherapy and reached platelet > 20 x 109/L after a median of 16 days (range 10‐33). Patients spent a median of 33 nights in hospital (range 14‐61; historical control 35 nights, range 31‐42; p = ns). After 2nd cycle, median days for ANC and platelet recovery were 29 and 26 (range 16‐45 and 13‐60 respectively, historical control for ANC recovery 20 days, range 18‐25; p = 0.001). Median patients’ hospitalization was 39 nights (range 26‐55; historical control 32.5 nights, range 24‐47; p = 0.003).Patients and historical controls received same antimicrobial prophylaxis in induction and experienced respectively 33/36 (91.7%) and 36/39 (92.3%) infective events. Patients had a higher number of infections of unknown origin (15/33 vs 6/36, p. 002), and lower incidence of Gram‐positive isolates (4/12 vs 15/22, p = 0.002). Any‐mould infection rate was comparable in the two groups.Twenty‐seven of 36 patients and 22/39 controls proceeded to consolidation chemotherapy. Antimould prophylaxis was different, with patients receiving mainly posaconazole 17/27 (63 %), fluconazole 5/27 (18.5%), itraconazole 4/27 (14.8%) and voriconazole 1/27 (3.7%); while controls received posaconazole 4/22 (18.2%) fluconazole 5/22 (22.7%), itraconazole 12/22 (54.5%) and voriconazole 1/22 (4.5%). Twenty‐two of 27 patients (81.5%) and 17/22 (77.3%) in controls had an infection. Three patients of 27 had a probable mould infection and 1 possible, compared to 1 proven mould infection and 1 possible in the 22 controls (any‐mould infection 4/27 vs 2/22).Summary/Conclusion:In our experience FLAI‐5 is associated with high CR rates, but prolonged neutropenia and hospitalization after 1st consolidation. However, this doesn’t translate in a higher infection risk in this set of patients.

Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial.

8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10-5) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (<18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL‐8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab‐containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non‐obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non‐obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.

Sequential CD22 Targeting Impacts CD22 CAR-T Cell Response

Background: With advances in immunotherapeutic approaches and the recognition of antigen modulation as a mechanism of relapse, it is imperative to understand the impact of sequential targeting strategies and the role it may have on outcomes of future therapies to optimize timing of therapeutic interventions. We previously reported on the safety, feasibility, and efficacy on our phase I dose escalation anti-CD22 CAR protocol (clinicaltrials.gov/NCT02315612).1 Based on our initial experience, we identified CD22 loss or diminution of CD22 as a risk factor for relapse following CD22 directed CAR therapy. With development of other CD22 directed therapies, we retrospectively analyzed impact of prior CD22 targeted therapy on response to CD22 CAR in our ongoing clinical trial.Design: Children and young adults with relapsed/refractory CD22+ hematologic malignancies eligible for our phase I dose escalation anti-CD22 CAR protocol were enrolled on study (Clinicaltrials.gov NCT02315612). All had bone marrow evaluations at baseline, prior to lympho-depleting chemotherapy (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) and again at day 28 (+/- 4 days) post-CAR infusion. We retrospectively analyzed the impact of prior CD22 directed therapy on outcomes following CD22 CAR and specifically looked at the variables of CD22 antigen expression prior to CAR infusion (% positive and antigen density) and compared responses to CD22 CAR for those who did and did not receive prior CD22 targeted therapy.Results: From December 2014 to July 2018, 43 subjects with ALL were treated. All had active bone marrow involvement at baseline, the majority with an M2 marrow (>5% blasts) or higher disease burden. 34 had a prior transplant and 26 were previously treated with CD19 CAR. Fourteen subjects had received prior CD22 directed therapy, including CD22 CAR elsewhere (n=2) or inotuzumab ozagamicin (Ino) (n=13). Subjects received a median of 3 doses of Ino (3-6 doses) and the median time from last Ino exposure was 2 months (range 1-20 months). Median CD22 antigen expression on bone marrow leukemic blasts prior to planned lymphodepletion for those who had received prior CD22 therapy compared to those who did not was 2527 (882-9079) vs 3929 (846-13452), respectively (one-tailed p=0.05, Figure 1). (Figure 1). Complete remission (CR) rates following CAR-T infusion for those who had prior CD22 directed therapy compared to those who did not was 57% and 71%, respectively with MRD negativity by flow cytometry achieved in only 5/8 (62.5%) patients versus 18/20 (90%) respectively and residual disease in those not achieving MRD negativity was CD22 dim. Both subjects who had received prior CD22 CAR elsewhere were non-responders to our construct with a first-infusion, however one subject converted to a CR with an intensified lymphodepletion and a second infusion. Two subjects who had received prior Ino were noted to have partial CD22 expression on at least one time point (69-89% positivity) prior to enrollment. One of these patients with pre-existing CD22 partial positivity (69% positivity) had evidence for CAR-T cell expansion but had residual low CD22 expressing disease at restaging. Notably, another subject who received 6 doses of Ino prior to receiving CD22 CAR T-cells and had uniformly CD22+ disease at enrollment, emerged with CD22 negative disease following CD22 CAR. Durability of remission also significantly differed amongst the two groups. Median time to relapse in patients who received prior CD22 directed therapy was 2 months (range 2-5 months) versus 6 months (range 2-13 months) for those who did not receive prior CD22 targeted therapy, with the majority relapsing with CD22 negative disease.Conclusion: Sequential targeting of CD19 has anecdotally increased the possibility of CD19 negative relapses, and our data provide evidence for a similar phenomenon with sequential targeting of CD22. Most notably, CD22 expression in patients who had received prior CD22 targeted therapies was lower compared to those who did not. This may have ultimately contributed to both of the observed findings of decreased response rates and decreased durability of remission, the majority of whom relapsed with CD22 negative disease following sequential targeting. This observation contributes to the increasing fund of knowledge regarding optimization of targeted therapies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prospective Analysis of Bortezomib, Fludarabine and Melphalan As Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation for Multiple Myeloma

Background: Despite advances in novel myeloma treatments and autologous hematopoietic stem cell transplantation (ASCT), allogeneic HSCT (alloSCT) remains the only curative option for patients (pts) with multiple myeloma (MM). Questions remain as to the timing of alloSCT, toxicity risks and optimal conditioning regimen. The addition of bortezomib (Vel) to fludarabine (Flu) and melphalan (Mel) for conditioning prior to alloSCT is based on the demonstrated safety of Vel in combination with melphalan prior to ASCT, the synergistic effect of Vel with Mel, and the ability of Vel to selectively eliminate allo-reactive T-cells. Methods: We present a prospective Phase II study using Flu/Mel/Vel (FMV) as a conditioning regimen for alloSCT. The primary endpoint is overall survival (OS), and secondary endpoints include progression free survival (PFS), incidence of graft-versus-host disease (GVHD) and transplant related mortality (TRM). For related donors, the conditioning regimen was Flu 30 mg/m2 days -5, -4, -3, -2, Vel 1.6 mg/m2 days -4, -1, Mel 140 mg/m2 day -2. For unrelated donors, rabbit ATG 4 mg/kg was given in divided doses days -3, -2, -1. GVHD prophylaxis consisted of methotrexate and tacrolimus. We compared pts receiving FMV to historical controls of pts receiving FM at the same dose and schedule without Vel. We also compared pts receiving FMV to all pts with MM treated with alloSCT including all regimens and donor types. The response criteria from the IMWG and M-Smart criteria were used to determine response and risk, respectively. Chi-square tests of association and Wilcoxon rank sum tests were performed to test for differences across groups. OS/PFS probabilities were calculated using the Kaplan-Meier product limit estimator with log rank-tests. Multivariate Cox proportional hazard models examined factors associated with OS/PFS. Results: Of the 54 pts who received FMV, 35 (65%) were male and the median age was 56 years. Twenty-seven pts had an HLA matched sibling donor and 27 had an unrelated donor. At the time of alloSCT, 5 pts were in a CR, 27 in a VGPR, 13 in a PR, 9 had Pts in the control groups had similar baseline characteristics to the FMV group. The only significant difference was 47 pts (72%) who received FM were transplanted as salvage, and 18 (28%) as consolidation after ASCT (p=0.035). The total number of pts who did not receive FMV (non FMV) was 121, with 66 pts receiving FM. Compared to pts who received FMV, there was no difference in OS for pts who received FM or the non FMV group, 35% (p=0.55) and 48% (p=0.855) respectively. There was no difference in pts who developed aGVHD, however 9 pts (13%) had ≥ grade 3 aGVHD in the FM group (p=0.004) and 15 (12%) in the non FMV group (p=0.006). The cumulative incidence of cGVHD was similar with 51% for pts receiving FM and 60% for FMV pts (p=0.32). TRM was similar to pts who had received FMV; 18% for FM and 17% for non FMV. There were no differences between the 3 groups across disease risk, donor type, or disease status at the time of alloSCT. Multivariate analysis of the 3 groups, shows achieving a CR after alloSCT (p=0.0006) or having cGVHD (p=0.0004) predicts for improved OS, while severe aGVHD (p=0.0002) predicts for decreased OS. Discussion: While FMV was associated with a lower incidence of severe aGVHD, the addition of bortezomib to the FM backbone did not improve PFS or OS. Day 100 TRM was low for all regimens, and the addition of Vel did not impact overall TRM. For all 175 pts, those who achieve a CR after alloSCT had a significantly improved OS. This prompts the question of whether strategies should be employed post alloSCT to maximize response to a CR, and the role of achieving MRD negativity after alloSCT also needs to be elucidated. Disclosures Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Biran:Amgen: Consultancy, Speakers Bureau; BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau.

Minimal residual disease is an independent predictor for 10-year survival in CLL

AbstractMinimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL.

Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)

Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)

Cladribine Combined with Idarubicin and Ara-C (CLIA) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

Cladribine Combined with Idarubicin and Ara-C (CLIA) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)

Bortezomib and High Dose Melphalan (Bor-HDM) Compared to HDM Conditioning for the Treatment of Transplant Eligible Multiple Myeloma: Report from a Single Center

Introduction Preclinical and clinical data suggest that bortezomib in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve the quality of response for MM patients undergoing auto-SCT. In the present study, we aimed to assess the impact of Bor-HDM conditioning on ORR, and MRD negativity for MM patients undergoing single auto-SCT at our Institution.Methods All consecutive patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2004 to 06/2015 using Bor-HDM or HDM as conditioning regimen were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. MRD negativity was assessed by multiparameter flow cytometry. All patients received induction chemotherapy before undergoing auto-SCT. Bortezomib was administered intravenously at 1-1.3 mg/m2 on days −5, −2, 1, and 4, while melphalan was given at 200 mg/m2 on day −1. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test.Results Two-hundred and fifty-eight consecutive patients receiving Bor-HDM or HDM alone were evaluated. A total of 85 patients received Bor-HDM conditioning and 173 received HDM. Clinical characteristics and chemotherapy induction regimens are listed in Table 1. At day-100 post auto-SCT a ³VGPR was seen in 83.3% in the Bor-HDM group compared to 67.6% for HDM patients. The CR/nCR rate was higher in the Bor-HDM group (47.6% vs 23.6%) as well as MRD negativity assessed by flow cytometry (30.9% vs 9.7%, p=0.0001). Median OS in the Bor-HDM group was NR compared to 95 months for HDM alone (p=0.572), while median PFS was 39.3 months for Bor-HDM compared to 27 months for HDM (p=0.1). Median OS was shorter in the HR cytogenetic group regardless of the type of conditioning regimen employed (39 months vs NR for SR cytogenetics). In addition, patients who achieved MRD negativity, exhibited a longer OS (NR vs 78 months, p=0.007). Transplant-related mortality (TRM) was similar between both groups (p0.5).In conclusion, Bor-HDM is a safe and efficacious conditioning regimen able to increase the nCR/CR and MRD negativity rates compared to HDM. Further studies are warranted to explore this regimen, especially when other upfront therapies are employed, with special view on the high-risk MM patients where response rates are good but sustainability remains an issue.Table 1Clinical CharacteristicsCharacteristicBor/HDM, N=85HDM alone, N=173Age (median)5859GenderMaleFemale51 (60%)34 (40%)113 (65.3%)60 (34.7%)Hb (g/L)112117Calcium (µmol/L)2.252.29Creatinine (µmol/L)8580B2microglobulin (µmol/L)3.32.79Albumin (g/L)3135Stage IStage IIStage III154723617333M-spike (g/L)3430LDH (IU/L)194180BMPC (%)4033Heavy chain:IgGIgAIgDFLC onlyBiclonalIgM4918115111142403210Light chain:KappaLambdaBiclonal50351124471High riskStandard risk226336135InductionCyBorDVDDexamethasoneRVD452401616544315 [Display omitted] [Display omitted] [Display omitted] DisclosuresJimenez-Zepeda:Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding.

Phase II Study of Cladribine and Low-Dose Cytarabine (AraC) Alternating with Decitabine in Older Patients with Acute Myeloid Leukemia (AML)

BackgroundIntensive chemotherapy is associated with poor tolerability and high early mortality in the treatment of AML in older patients. Lower intensity approaches using hypomethylating agents have been developed in patients with lower bone marrow (BM) blast counts, but more effective therapies are needed, particularly in those with higher BM blasts. Cladribine, which itself may have hypomethylating properties, has single-agent activity in AML. Cladribine has also been shown to improve survival in AML in combination with standard-dose araC (Holowiecki JCO 2012).MethodsWe developed a low-intensity, prolonged-maintenance treatment protocol studying the combination of cladribine and low-dose araC (LDAC) alternating with decitabine in patients aged ≥ 60. Patients with adequate organ function and newly diagnosed AML (except APL), including secondary- (s-AML) and therapy-related AML (t-AML), and high risk MDS were eligible. Induction consisted of cladribine 5 mg/m2 IV over 30 minutes on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV over 30 minutes on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of decitabine 20 mg/m2 on days 1-5, for a maximum of 18 cycles. One cycle was 4 weeks and up to 2 cycles of induction were allowed.ResultsA total of 74 patients have been enrolled with a median age of 69 years (range, 49-85), including 33 pts (45%) ≥ age 70. 41 pts (55%) had secondary- (s-AML) or therapy-related AML (t-AML) and 14 pts (19%) had therapy for an antecedent hematologic disorder. Patient characteristics are listed in table 1. Of the 74 pts evaluable for response, there were 42 CR (57%), 6 CRp (8%), and 3 PR (4%) for an overall response rate of 69% (51/74). 43 patients (58%) had BM blasts ≥ 30%, and they had a CR/CRp rate of 67%. Of the 43 patients who achieved a CR/CRp and had minimal residual disease testing (MRD) by flow cytometry, 28 patients (65%), achieved MRD negativity at the time of CR or later. AML mutation screening was performed prior to treatment. Ten of 10 patients (100%) with FLT3-mutated AML and 13/13 (100%) pts with an NPM1 mutation achieved a CR/CRp. With a median follow-up of 11+ months, the median OS is 12.7 months and the median CR duration is 13.1 months. (Figure 1) The 1-year OS estimate is 57%. The regimen was very well tolerated, with 1% 4-week mortality. There were no treatment-related grade 3/4 non-hematologic adverse events (AEs). Most common non-hematologic AEs were elevated bilirubin, nausea/vomiting, rash/itching, diarrhea and mucositis.ConclusionThe low intensity program of cladribine + LDAC alternating with decitabine is a highly effective, well-tolerated ambulatory regimen for older patients, including those with unfavorable-risk features. Patient samples are being analyzed for methylation changes on treatment.Table 1Patient Characteristics (N=74)CharacteristicN (%)Median age [Range]69 [49-85]CytogeneticsDiploid21 (28)Adverse30 (41)-5/-723 (31)Complex without -5/-77 (9)Misc. other17 (23)Insufficient6 (8)MutationsNPM113/69 (19)FLT3-ITD8/69 (12)RAS15/69 (22)Median BM Blast [Range]32 [8-95]Median WBC [Range]2.5 [0.5-72.3]Median Platelets [Range]40 [4-772]Median Peripheral Blasts [Range]6 [0-88]Median LDH [Range]742 [301-8425]Median Creatinine [Range]0.91 [0.46-1.94]Median Bilirubin [Range]0.6 [0.2-2] [Display omitted] DisclosuresKantarjian:ARIAD, Pfizer, Amgen: Research Funding.

A Phase II Study of Weekly Inotuzumab Ozogamicin (InO) in Adult Patients with CD22-Positive Acute Lymphoblastic Leukemia (ALL) in Second or Later Salvage

▪Background: InO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on the majority of cells derived from patients (pts) with B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Kantarjian, et al. Cancer. 2013;119(15):2728-36).Aims: This ongoing study was preceded by phase 1 dose-escalation and expansion cohorts to select the recommended phase 2 dose (RP2D), determined as 1.8 mg/m2/cycle (0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15) as an initial starting dose followed by a dose reduction to 1.6 mg/m2/cycle upon achievement of complete response (CR) or CR without absolute neutrophil count (ANC) or platelet recovery (CRi). One dose-limiting toxicity (elevated lipase) was reported at this starting dose; however, dose delays and reductions were subsequently required in 5 patients for AEs (mostly owing to increased aspartate aminotransferase [AST]). Here we report the results of the phase 2 portion of the study which further evaluates the safety and efficacy of this regimen in patients with CD22+ relapsed/refractory ALL in the second and later salvage settings.Methods: Pts aged ≥18 y with CD22+ ALL in second or later salvage and no known central nervous system disease were enrolled. InO was administered in 28-d cycles up to 6 cycles. Adverse event (AE) severity was assessed per Common Terminology Criteria for Adverse Events (CTCAE) v3. CR was defined as <5% bone marrow blasts without peripheral blasts, ANC ≥1,000/µL, platelets >100,000/µL and no extramedullary disease. Blood samples were collected for pharmacokinetic analyses.Results: We report data for 35 pts: median age was 34 y (range, 20–79y); 77% were men; 6 (17%) pts were in salvage 5 or greater; 15 (43%) pts had prior allogeneic stem cell transplant (SCT). CD22 was expressed on a median of 99% blasts (range, 78%–100%); median peripheral blast count was 317.6/µL (range, 0–41,099/µL) and 28 (80%) pts presented with ≥50% bone marrow blasts. Aberrant baseline cytogenetics were reported in 27 (77%) pts including 9 (26%) with Ph+, 9 (26%) with complex cytogenetics (5 aberrations) and 9 (26%) with other aberrations. Three pts had normal cytogenetics at baseline and 5 had insufficient yield/unknown. Median follow-up in surviving pts was 4.4 (range, 0.7–11) months. Thirty-four pts discontinued InO: 17 owing to progressive disease (PD)/relapse or resistant disease; 7 proceeded to SCT (1 relapsed before SCT); 5 owing to AEs (grade [gr] 4 respiratory failure, gr 2 ascites in the setting of global deterioration, gr 2 increased alkaline phosphatase, gr 2 elevated AST and gr 2 increased transaminases); 2 died due to PD; 1 completed 6 cycles of InO and proceeded to maintenance therapy; 1 refused further treatment and 1 proceeded to DLI. InO-related gr ≥3 AEs (≥10% of pts) were thrombocytopenia (31%), neutropenia (26%) and febrile neutropenia (20%). Other gr ≥3 hepatic AEs included increased ALT/ increased transaminases (6%). Venoocclusive disease/sinusoidal obstruction syndrome occurred in 3 pts during the follow-up period: 2 (salvage 2 and 5) post-SCT and 1 (salvage 4) after the start of subsequent therapy. Prestudy SCT was not reported for these 3 pts. Nineteen deaths were reported: leukemia (n=14), hepatic failure/SOS (n=1), pneumonia (n=1), septic shock and graft versus host disease (n=1), subdural hematoma (n=1), and leukemia/liver failure (n=1).The remission rate (CR+CRi) was 65.7% (95% CI, 47.8, 80.9); 18/23 (78%) patients with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 25 d (range, 15–86 d) and 25.5 d (range, 21–80 d), respectively. Six (67%) Ph+ pts and all 13 pts (100%) without peripheral blood blasts at baseline achieved CR/CRi. The median overall survival for the study population was 7.4 months (95% CI, 4.3–9.9).Summary/Conclusion: InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this multiply relapsed/refractory population. Further exploration in CD22+ ALL is ongoing.Table 1Median (range) InO cycles initiated, n3 (1–6)CR + CRi rate, n (%) [95% CI]23 (65.7) [47.8, 80.9]CR11 (31.4)CRi12 (34.3)MRD negative rate in pts with CR/CRi, n (%)18 (78.2)CR (n=11)8 (73)CRi (n=12)10 (83)OS (95% CI) at 12 mo, %26 (10, 50)Median (95% CI) OS, mo7.4 (4.3, 9.9) DisclosuresAdvani:Pfizer Inc: Research Funding. Kantarjian:Pfizer Inc: Research Funding. DeAngelo:Pfizer Inc: Advisory Board Other. Ananthakrishnan:Pfizer Inc: Employment. Liau:Pfizer Inc.: Employment. Vandendries:Pfizer Inc.: Employment. Stock:Amgen: Consultancy; Sigma Tau: Consultancy; Jazz: Consultancy; Seattle Genetics: Consultancy; UpToDate: Honoraria; American Board of Internal Medicine: Honoraria.

Combination Imatinib with Interferon-α For Philadelphia Positive Acute Lymphocytic Leukemia: A Mutiple Centers Study In China

BackgroundImatinib combined with chemotherapy for induction and intensification therapy has become the standard strategy for Philadelphia-positive acute lymphocytic leukemia (Ph+ALL). Anyhow, intensified chemotherapy lead to about 5% of early death. Because we believed that imatinib plays the most important role in Ph+ALL treatment, we started Ph+ALL-HX-200803 trial (WHO ICTRP Registry No. ChiCTR-TNRC-00000309 ) to test the effect of combining imatinib and low dose chemotherapy and added interferon-¦Á in maintenance to prevent relapse. MethodAccording to our protocol, all patients received imatinib 400mg daily, vindesine 4 mg weekly and dexamethasone 10mg/m2/day for 4 days per week for 4 weeks as induction therapy. For patients under 55 years old, we give them three sequential courses of intensified chemotherapy (CAM, high dose MTX+L-Asp, and MA, CALLG2008 protocol). Patients in CR1 would receive allogenic HSCT if they had suitable donors. Those who were reluctant to receive or unsuitable for allo-HSCT received maintenance therapy with imatinib 400mg daily, interferon-¦Á 3 million unit 2-3 doses per week and chemotherapy. Maintenance chemotherapy including vindesine and dexamethasone was given monthly in the first year, once every two months in the second year, and once every three months in the third year. For patients over 55 years old, we skipped intensified chemotherapy and gave them maintenance therapy directly. Minimal residual disease surveillance was conducted by BCR/ABL fusion gene quantification. The main endpoints were 3-year overall survival and disease free survival. ResultBetween 2008 and 2012, 50 patients with newly diagnosed Ph+ALL were enrolled. The median age of this group of patients was 35.5 years old. All but one patients achieved complete remission (98%) after 4 weeks induction therapy. No patient died during induction therapy. The median follow-up time was 27 months. The estimated 3-year DFS and OS were 38.8 ±9.2% and 52.7±10.4%. Five patients received allo-HSCT in CR1. For patients who did not receive allo-HSCT in CR1, 1 patient survived for more than 5 years, 7 patients survived for more than 3 years. In post-hoc analysis, patients achieved MRD negativity at six month showed better median DFS (not reached vs. 11 moths, p=0.001) and OS (not reached vs. 22 months, p=0.015) compared to those who did not. ConclusionThe outcomes of our study suggest that imatinib combing with low dose chemotherapy showed a high and safe induction remission rate, combination of interferon-¦Á with imatinib and maintenance chemotherapy might improve the outcomes of patients with Ph+All who were not eligible for Allo-HSCT. MRD status at six month is an important prognostic indicator. The long term disease-free survivors may signal the possibility of a cure even without allo-HSCT. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Evaluation of MRD Status by Flow Cytometry and PCR in Multiple Myeloma Elderly Patients Receiving Autologous Stem Cell Transplantation After Bortezomib-Supplemented Mobilization and Conditioning

AbstractAbstract 4523Autologous Stem Cell Transplantation (ASCT) is still an option for eligible patients with Multiple Myeloma (MM). High-dose melphalan (HDM: 200mg/m∧2) is the recommended conditioning before ASCT, but synergistic effects of Bortezomib (BOR) and HDM have been reported in vitro and in vivo. PATIENTS AND METHODS:We evaluated in 56 MM fit elderly patients (median age 65 yrs), the feasibility and efficacy (also in terms of evaluation of minimal residual disease: MRD) of a strategy, combining BOR, Cyclophosfamide (CY) and dexamethasone (DEX) as induction and mobilizing therapy (CY-BOR), for ASCT, with conditioning including BOR-HD-MEL. The patients achieving at least PR after 4 CY-BOR courses, were mobilized with BOR and DEX standard schedule with CY 3g/m∧2 (day 8). The pts collecting at least 2.5×10∧6CD34+/kg underwent ASCT with HD-MEL (day-1) and BOR (1.0mg/m∧2 on -6,-3,+1,+4), followed by thalidomide consolidation until Relapse/Progression. The MRD has been prospectively evaluated both by using 4 colour flow cytometry (FC), and by using patient-specific probes, by ASO-PCR. The percentage of plasma cells (PCs) has been evaluated both in in PBSC harvested and in bone marrow, with CD38, CD45, CD56, CD138, CD19, CD27, CD28, CD117, kappa and lambda, along different steps of therapy. RESULTS:Of 44 pts evaluable for response before ASCT, 32 (73%) achieved 3PR and 30 (68%) were mobilized: 29 (66%) collected3 2.5×106CD34+/kg and 25 underwent ASCT. Median time for PMN engraftment was 11 days (range 10–13) and 14 (range12–20) for PLT>=20.000/mcl. We observed grade 3 neuropathy in 3 patients and pneumonia during induction in 2 patients. At day +180 from ASCT 23 are evaluable for response and 21 for MRD: 3 pts have progressive disease (PD), 2 pts have a PR, 4 pts have a VGPR, 10 pts a nCR and 4 pts a CR. Four colour FC, in order to detect clonal plasmacells (cPCs) along several steps of treatment, showed that 3 pts (14%) achieved MRD negativity: 1/21 pts achieved MRD negativity at day +180 (cPC <0.01%), being positive after induction and at day +90 after ASCT; two patients were MRD negative after induction (one developed positivity at day + 180 and relapsed at day +365 from ASCT; the other one became positive at day +90 after ASCT and, is in CR at 10 months from ASCT). In 5 patients we evaluated MRD by PCR with patient-specific probes. One patient achieved clearance of MRD after induction and still maintains negative of PCR at 27 months from ASCT: this patient had positivity of MRD by flow cytometry after induction and at 90 months from ASCT, then became negative and is in CR. One became PCR negative after ASCT: flow cytometry was negative too and the patient is in CR at 10 months from ASCT; the remaining three patients are PCR positive: two of them experienced progression of disease. CONCLUSIONS:ASCT with HDM and BOR is feasible in older patients, with very high RRs and without major toxicities. We need a longer follow up and a larger number of pts to assess if these results will translate in a benefit in terms of outcome. Disclosures:Fragasso:Mundipharma: Honoraria.

Long Term Survival Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab In Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group)

AbstractAbstract 922 Background AND TRIAL DESIGN:Patients with fludarabine refractory chronic lymphocytic leukemia (CLL) have a very poor prognosis with conventional chemotherapy with a median survival of 10 months and <10% surviving for 5 years. In 2006 the results of the response assessment of a multicenter phase II (UKCLL02) trial of subcutaneous (SC) alemtuzumab in fludarabine refractory CLL (defined as failing to respond to, or relapsing within 6 months of, fludarabine containing therapy) were presented, showing an overall response rate of 49%. We now report the survival data after a median follow up period of 64.6 months. SC alemtuzumab was given at a dose of 30mg 3x a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. Results:53 patients were enrolled but 2 patients died before receiving alemtuzumab and 1 withdrew consent. 50 patients have completed therapy (median duration of alemtuzumab was 18.8 months with a median dose of 1370mg [106-2323mg]). Response assessment was possible in 49 patients of which 8 patients achieved a complete remission (CR) and 16 patients achieved a partial remission (PR) giving an overall response rate of 49%. 17 patients had fludarabine added to the alemtuzumab (6 PR, 11 non-responders [NR]) and 3 had an improvement in response (1 from PR to CR and 2 from NR to PR). Median overall survival (OS) was 20.2 mo (CI 95%, 13.2–27.1) and progression free survival (PFS) was 13.0 mo (CI95%, 10.3–15.7). The 5-year OS and PFS rates were 24% and 9% respectively. Patients who achieved a CR, PR and less than a PR had a median OS of 63.6 mo, 20.2 mo and 18.2 mo, respectively and a median PFS of 47.1 mo, 13.8 mo and 7.5 mo respectively. Of 18 patients evaluable for MRD status, 7/18 achieved an MRD negative response and 11 were MRD positive with OS of not reached vs 13 mo (p=.02) and PFS of 47.1 vs 22.3 mo (p=.02), respectively. Of the 7 patients achieving MRD negativity, 5/7 (71%) were alive at 5 years. The IGHV gene was unmutated (>98% germ line homology) in 23/31 evaluable patients. Comparing unmutated with mutated for OS gave 18.2 and 13.1 mo (p=0.3) and PFS of 16.6 and 12.3 mo (p=0.08). FISH revealed poor risk deletions (11q and/or 17p) in 21/45 patients (17p- in 10, 11q- in 8, both in 3). 25/38 patients had dysfunction p53 in a functional assay previously reported by Pettitt et al (Blood, 2001; 98: 814–822). The table shows the lack of impact on PFS and OS.AbnormalitystatusOverall SurvivalProgression Free Survivalp53Deleted (n=13)13.4P=0.512.3P=0.8Normal (n=32)19.213.0P=0.4p53Dysfunctional (n=25)16.7P=0.212.3Wild type (n=13)20.812.0P=0.8ATMDeleted (n=11)18.6P=0.811.3Normal (n=34)20.812.6P=0.3All poor riskPoor risk (n=32)19.9P=0.812Without (n=16)20.813In addition to prospective FISH evaluation we have performed retrospective SNP microarray using Illumina human CytoSNP-12 BeadChip on stored bone marrow and peripheral blood slides. Each BeadChip includes a complete panel of genome-wide tag SNPs and markers (>330,000 in total) targeting all regions of known cytogenetic importance. 36 patients were tested, SNP analysis identified all of the deletions present in more than 20% of CLL cells detected by FISH except in 1 patient due to technical issues. SNP analysis identified 2 additional patients with abnormalities in 17p (one deletion and one copy neutral loss of heterozygosity) and 2 more with deletions in 11q. A number of other chromosomal aberrations (average number per patient =2.6, with a maximum of 12 in one patient) were also detected although no recurrent abnormalities were identified. Summary:We report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL. In this group, patients with poor risk deletions havenÕt got a survival disadvantage over the non deleted group presumably because all of the patients were resistant to conventional chemotherapy regardless of whether a p53 pathway abnormality could be detected. SNP microarray is a useful research tool in studying genomic aberration from archived bone marrow and blood samples including in stored blood and marrow slides. The long term survival data shows that subcutaneous alemtuzumab improves the OS and PFS in fludarabine refractory CLL particularly in patients achieving MRD negative remissions. [Display omitted] Disclosures:Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pettitt:Glaxo Smith Kline: Research Funding. Kennedy:Roche Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

NCRI CLL201 Trial: A Randomized Phase II Trial of Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) with or without Rituximab in Previously Treated CLL.

Standard front-line therapy for chronic lymphocytic leukemia (CLL) is fludarabine plus cyclophosphamide. Adding mitoxantrone (FCM) or rituximab (FCR) appears to improve responses although no large randomized trials have been reported. We report a randomized Phase II trial of FCM and FCM-R in relapsed CLL. FCM was oral fludarabine (24mg/m2 for 5 days) and cyclophosphamide (150mg/m2 for 5 days) plus i.v. mitoxantrone (6mg/m2) on Day 1 of each cycle. FCM-R was identical with rituximab on Day 1 of each cycle (375mg/m2 cycle 1; 500mg/m2 cycles 2 to 6). Prophylaxis with aciclovir and co-trimoxazole was given. The primary end-point was response by NCI Criteria 2 months after therapy. Complete remission with incomplete marrow recovery (CR(i)) was defined according to the 2007 CLL Guidelines - clinical CR with a morphologically normal marrow but persistent cytopenias (i.e. platelets <100x109/l and/or neutrophils <1.5x109/l). In addition, minimal residual disease in the marrow was studied 2 months after therapy by four-color flow cytometry with MRD negativity defined as <0.01% CLL cells. 52 patients were entered into the trial with 26 in each arm. The median age was 65 (32–79) with 79% men. 42% had a β2m >4. The median number of prior therapies was 2 (1–6), 31 had prior fludarabine and 6 (12%) were refractory to or relapsed <6 months after fludarabine. 26/44 (59%) had unmutated VH genes (15/22 FCM-R; 11/22 FCM). 11 patients had deletion of 11q (FCM-R 5, FCM 6) and 1 patient had >20% 17p deleted cells (FCM-R). 36/52 (69%) received 4 or more cycles of therapy with no difference between FCM and FCM-R (18/26). Responses are shown in the Table. 35 SAE's were reported in 23 patients. There was no difference in the number of patients with SAE's between the arms (FCM 11, FCM-R 12). 6/7 patients (86%) who had 4 or more prior therapies reported an SAE, compared to 17/45 patients (38%) who had less than 4. 16 SAE's were suspected to be related to FCM-R and 10 related to FCM. In summary, FCM-R is an effective therapy for relapsed CLL with over two-thirds of patients responding. The study design does not allow a statistical comparison between FCM and FCM-R but the results suggest that adding rituximab to FCM results in a higher complete response rate (CR + CR i = 43% for FCM-R and 13% for FCM) with more patients achieving MRD negativity (5 after FCM-R; 2 after FCM). The results of this randomised Phase II trial justify the study of FC with mitoxantrone and/or rituximab in larger randomized Phase III trials.Responses in 46 evaluable patients (remaining 6 not yet evaluable)All patientsFCMFCM-RNumber of patients462323Overall response rate29 (63%)13 (57%)16 (70%)CR5 (11%)1 (4%)4 (17%)CR(i)8 (17%)2 (9%)6 (26%)PR16 (35%)10 (43%)6 (26%)SD/PD12 (26%)7 (30%)5 (22%)Early Death (before assessment)4 (9%)2 (9%)2 (9%)Withdrew consent (before assessment)1 (2%)1 (4%)0 (0%)MRD negative7 (15%)2 (9%)5 (22%)

Planned First Safety and Efficacy Analysis of Oral Fludarabine Combined with Subcutaneous Alemtuzumab in 2nd Line Therapy of B-Chronic Lymphocytic Leukaemia (B-CLL): The FLUSALEM Study.

Background: In a previously published small-scale pilot study, the chemoimmunotherapy combination of alemtuzumab (Campath®)and fludarabine was effectively used in heavily pre-treated patients. The positive responses in 5 of 6 patients treated, and even among those that were unresponsive/refractory to either single-agent therapy, was attributed to the potentially synergistic activity between alemtuzumab and purine analogues (Kennedy, Blood, 2002). Although typically administered intravenously, following a dose escalation, alemtuzumab administered in a subcutaneous (SC) manner has been shown to significantly reduce the infusion-related toxicities. Here we present the first planned analysis of Fludarabine in combination with SC alemtuzumab in second line CLL therapy.Methods: Patients with active CLL who had failed 1 regimen of therapy were treated with 4 cycles of oral fludarabine (30mg/m2 for 1–3d) and sc alemtuzumab 30 mg, 3 times per week for 16 weeks (FLUSALEM). The study follows a 2-step Gehan design, which features an early interim analysis after 7 patients have completed four cycles of concomitant therapy, to define minimally required efficacy and to facilitate protocol modifications. We evaluate feasibility, the safety profile and initial response rates.Results: The results of the first 7 patients enrolled in the trial are presented. Clinical response was very fast and 5/7 Patients were in clinical CR, according NCI-WG 1996 criteria, also confirmed by CT-scan, after only 2 cycles of therapy. On an intent to treat basis, the overall response rate was 85% and the CR rate at the end of therapy was 85% (including evaluation of BM biopsy). MRD analysis was performed using a 4-colour flow cytometric assay. All evaluable patients who completed full course of therapy, (N=6) achieved MRD negativity usually within 2 cycles of therapy. One patient discontinued early due to a violation of inclusion criteria and pneumonia at the start of therapy. No tumor lysis syndrome was observed. Thirteen Grade III–IV adverse events were reported, and 3/7 patients (37%) developed clinically manageable CMV-reactivations, as was evidenced by a fever. The main other reason for hospitalization was pneumonia. Grade III–IV neutropenia was observed in 6/7 patients, however in most cases it was associated with initial BM infiltration and resolved quickly with treatment. A total of 4 febrile episodes were observed and only one patient required transfusions for anemia and no platelet transfusion was needed. For all patients the protocol was feasible on an out patient basis with weekly visits. An evaluation of quality of life questionnaires is planned after all 28 patients, which are planned to be recruited for this study, complete therapy.Conclusions: We present a first planned interim analysis of the investigator initiated FLUSALEM pilot study. This protocol is being conducted on an out patient basis and shows very rapid responses with deep remissions. The therapy has manageable toxicity and may represent an attractive therapeutic approach in pretreated patients with CLL.