ALBERT

Description: Abstract 1702 Poster Board I-728 Background ASCT consolidation in the first remission is the treatment of choice in MCL patients. However lack of adequate response to the first line therapy, elderly age and co-existing co-morbidities makes it feasible for less than a third of patients. Methods Retrospective analysis of 279 MCL cases treated at 10 PLRG centers was performed: 52% of them (144 pts) received Rituximab in induction therapy; 35% (97 pts) were subjected to post-induction therapy (ASTC – 16%, radioimmunotherapy consolidation – 13% and Rituximab maintenance – 6%). There were no significant differences in risk factor distribution among analyzed subgroups. Results 1) At 5 years OS was 40% in the whole group: 77% for those subjected to post-induction therapy vs 25% for those who were not; 5 year PFS is 20%, 48% and 5% respectively (p

Description: Our previous PALG study in 445 de novo AML patients has demonstrated that addition of cladribine to the standard daunorubicine-cytarabine (DA) remission induction regimen - DAC has a beneficial influence on both the CR rate after one induction cycle (p=0,0008) and on survival in patients older than 40 y (Leukemia2004,18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003). The goal of this study was to evaluate the efficacy of original combination including another purine analogue fludarabine – DAF (daunorubicine 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 iv d 1–5) in untreated patients with AML, aged up to 60 y, based on head to head comparison with DAC - (DNR, AraC, Cladribine), and standard DA regimens. We evaluated earlier the DAF protocol in relapsed or refractory AML (PALG pilot study; Ann Hematol.2008, 87:361–7. Epub 2007 Dec 12); the tolerance was good, CR 44%, LFS 38%. Primary objectives of the presented trial were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Additional analysis was planned for patients submitted to an early bone marrow allotransplantation (alloBMT) after CR. Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Between 09.2004 and 05.2008, 673 adult untreated AML patients aged 18–60 y, median 47 y, sex: male 49,5%, female 50,5%, treated in 18 co-operating Polish Adult leukemia Group (PALG) centres were centrally randomised to either DAF (n=225), DAC (n=224) or DA (n=224) arm (1:1:1). PML/RAR alfa positive - FAB M3 cases were excluded. The study groups were well balanced in respect of age, sex, FAB subtype, and WBC. After a single induction course the CR rate for patients receiving DAC equalling 63% was significantly higher if compared with DA - 51% (p=0,01), whereas no significant differences were noted between DAC vs. DAF - 55% and DAF vs. DA subgroups. Also the entire CR rate of 68% in the DAC arm was higher in comparison with DA one - 57% (p=0,02). No significant differences were found between DAC vs. DAF - 60%, and DAF vs. DA. At median time of 24 months (longest observation time 3,5y) the OS rate equalled 51% for the DAC treated subgroup and was higher in comparison to the standard DA arm - 39% and the DAF arm - 36% (p=0,03). The leukemia free survival rates (LFS) in DAC, DA and DAF treated cohorts equalled 51%, 32% and 41% respectively (p=NS). The early death rates of 8–10%. were similar in the studied treatment subgroups. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhoea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. In conclusion, this randomised study proves that the addition of cladribine to the standard DA induction regimen (DAC) improves CR rate and the overall survival in adults with AML aged up to 60 y, without additional toxicity. This beneficial effect was not observed in patients treated using the DAF protocol with fludarabine added to the standard “DA 3+7” schedule

Description: Background AFM11 is a bispecific, tetravalent T cell-engaging antibody construct binding to CD19 on B cell origin malignant cells such as B-precursor acute lymphoblastic leukemia (B-ALL) and to CD3 on T cells. By engaging CD3-positive T cells, AFM11 elicits T cell-mediated killing of CD19-positive (CD19+) leukemia and lymphoma cells. In vivo anti-tumor activity of AFM11 was investigated in a Raji tumor xenograft model in non-obese diabetic/severe combined immunodeficiency (NOD/scid) mice reconstituted with human peripheral blood mononuclear cells (PBMC). Tumor growth in all AFM11-treated animal groups was significantly reduced. In the highest dose group, all animals achieved complete tumor remission. (Reusch et al., 2015). An ongoing Phase 1 study assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AFM11 in patients with relapsed/refractory (R/R) CD19+ B-ALL. Methods Patients (pts) with relapsed or refractory CD19+ B-ALL are being enrolled into escalating cohorts of 1-6 pts. The primary objective of the study is to determine the maximum tolerated dose (MTD) of AFM11 administered as a 2-week continuous intravenous (CIV) infusion. AFM11 is administered over the first 2 weeks (wks) of each 4 wk cycle for up to 3 cycles. Pts with rapidly progressing disease receive pre-treatment with 200 mg cyclophosphamide and 10 mg/m2 dexamethasone over 3-5 days before initiating AFM11. A lower starting dose is employed during the first wk of cycle 1 and escalated to a target dose during the second wk of cycle 1 and all subsequent cycles. An accelerated titration design is used until toxicity is observed, followed by a classical 3+3 design. PD activity is assessed by flow cytometry of peripheral blood lymphocytes and serum cytokine measurements. Tumor response is evaluated by local bone marrow and peripheral blood laboratory results between days 15 and 18 of each cycle. Results As of June 29, 2018, fourteen pts (8 female/6 male) have been treated in 5 cohorts. The median age is 41.5 years (range 19-67) and the median number of prior therapies is 5 (range 1-12). AFM11 was well-tolerated with no dose-limiting toxicities (DLTs) observed in the first 5 cohorts. The study switched to 3+3 design in cohort 3 due to the occurrence of grade 2 AFM11-related events in cohort 2. Enrollment into cohort 6 is ongoing and the MTD has not yet been reached. The most frequent (≥2 pts) AFM11-related adverse events were pyrexia (29%), myalgia (14%), and tremor (14%). Most of the events were Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade 1-2, with one grade 3 and no grade 4 events observed. Transient and reversible neurological events occurred in 3 of 14 (21%) pts: grade 1 paresthesia (n=1), grade 1/grade 2 tremor (n=1 each), grade 2 lethargy (n=1); and grade 3 altered state of consciousness (n=1). The grade 3 event occurred during the third cycle of treatment and was managed with treatment interruption and steroids and resolved within 48 hours. The pt then completed the third cycle at a reduced AFM11 dose without incident. Peripheral B cell reductions were observed in multiple pts in cohorts 4 and 5 and notable cytokine release was detected in two pts. Two pts achieved complete remission with complete hematological recovery (CR): one pt in cohort 4 achieved CR after the first cycle and progressed 2 wks later; one pt in cohort 5 achieved CR after the first cycle which was sustained after the second and third cycles and was assessed as minimal residual disease (MRD) negative after cycle 3. As a result, this pt became eligible to receive stem cell transplantation upon study completion. Both CR pts had peripheral B-cell aplasia after the first few days of treatment. Updated data will be presented. Conclusions The CD19/CD3-targeting tetravalent bispecific T cell engager AFM11 was well-tolerated in pts with R/R B-ALL across the first 5 cohorts of an ongoing Phase 1 study, and the MTD has not been reached. Pyrexia was the most frequently observed related adverse event. Transient neurological events were observed and were consistent with those associated with other CD19-targeted therapies. Peripheral B cell reductions and complete remissions observed in pts treated in the higher dose cohorts suggest that AFM11 is active in pts with R/R B-ALL and that the study is nearing determination of the therapeutic dose and schedule. Disclosures Salogub: Affimed: Research Funding. Mayer:Novartis: Research Funding; Roche: Research Funding; Eisai: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Folber:Affimed: Research Funding. Grosicki:Affimed: Research Funding. Skotnicki:Affimed: Research Funding. Prochwicz:Affimed: Research Funding. Myasnikov:Affimed: Research Funding. Gural:Affimed: Research Funding. Schoenborn-Kellenberger:Affimed: Consultancy. Brindley:Affimed: Consultancy. Knackmuss:Affimed: Employment. Schwarz:Affimed: Employment. Schmich:Affimed: Employment. Choe-Juliak:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Doubek:AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Affimed: Research Funding; Novartis: Consultancy.

Description: Abstract 3746 Poster Board III-682 Background Mantle cell lymphoma (MCL) is a rare subtype (3-9%) of Non Hodgkin Lymphoma (NHL) with a relatively poor prognosis (5-year survival 〈 40%). Although consolidation of first remission with autologous stem cell transplantation (ASCT) is regarded as “golden standard”, less than half of the patients may be subjected to this intensive treatment due to advanced age and co-morbidities. Standard-dose non-myeloablative radioimmunotherapy (RIT) seems to be a very efficient approach for treatment of certain NHL. However, there are almost no data available on the efficacy and safety of RIT in MCL. Methods and Patients In the RIT-Network, a web-based international registry collecting real observational data from RIT-treated patients, 115 MCL patients treated with ibritumomab tiuxetan were recorded. Most of the patients were elderly males with advanced stage of the disease: median age – 63 (range 31-78); males – 70.4%, stage III/IV – 92%. RIT (i.e. application of ibritumomab tiuxetan) was a part of the first line therapy in 48 pts. (43%). Further 38 pts. (33%) received ibritumomab tiuxetan after two previous chemotherapy regimens, and 33 pts. (24%) after completing 3-8 lines. In 75 cases RIT was applied as a consolidation of chemotherapy induced response; the rest of the patients received ibritumomab tiuxetan because of relapse/refractory disease. At the moment follow up data are available for 74 MCL patients. Results After RIT the patients achieved high response rate: CR 60.8%, PR 25.7%, and SD 2.7%. Only 10.8% of the patients progressed. For survival analysis many data had to be censored since the documentation had not been completed yet. The projected 3-year overall survival (OAS, fig.1 – image 001.gif) after radioimmunotherapy was 72% for pts. subjected to RIT consolidation versus 29% for those treated in relapse/refractory disease (p=0.03). RIT was feasible for almost all patients; only 3 procedure-related deaths were reported in the whole group. The main adverse event was hematological toxicity (grade III/IV cytopenias) showing a median time of recovery of Hb, WBC and Plt of 45, 40 and 38 days respectively. Conclusion Standard-dose non-myeloablative RIT is a feasible and safe treatment modality, even for elderly MCL pts. Consolidation radioimmunotherapy with ibritumomab tiuxetan may prolong survival of patients who achieved clinical response after chemotherapy. Therefore, this consolidation approach should be considered as a treatment strategy for those, who are not eligible for ASCT. RIT also has a potential role as a palliation therapy in relapsing/resistant cases. Disclosures: Off Label Use: Ibritumomab Tiuxetan (Zevalin) for MCL.

Description: Panobinostat (LBH589), a novel cinnamic hydroxamic acid analogue with potent pan deacetylase inhibitor activity, acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. Panobinostat induces degradation of wild-type BCR-ABL, as well as BCR-ABL with the T315I and the E255K mutations in BaF3 cells. It also induces apoptosis in primary patients CML-BC cells. Panobinostat was investigated for the first time in patients (pts) in AP or BC stage of a Ph1+ CML in this Phase II trial. Panobinostat was dosed orally, 20 mg, once-a-day, thrice weekly. Concomitant hydroxyurea was permitted for up to 7 days within 14 first days in Cycle 1. Primary objective was to assess hematologic response rate, ie, complete hematologic response (CHR) with no evidence of leukemia (NEL) or return to chronic phase (RTC). Response confirmation was required after 4 weeks. As per protocol, to avoid futility for pts, efficacy cut-off required to move to Stage 2 enrollment was of 3 or more major cytogenetic responders (MCyR) out of the first 25 treated pts in Stage 1. A total of 27 pts, 13 female/14 male, with Ph+ CML who had failed ≥2 prior BCR-ABL tyrosine kinase inhibitors (TKIs), were enrolled into Stage 1 cohort of the study. Median age at entry was 55 years (29–76). Patients entered with a disease stage of AP or BC of 17/10, respectively. Time since initial CML diagnosis was ≥5 years in 59% of pts. The majority of pts (55%) had evolved into their current disease stage (AP or BC) within the year prior to entry. Best response under TKIs, at any disease stage, had been cytogenetic response (CyR) in 8 pts, complete hematologic response (CHR) in 9 pts, and finally, no CHR in 10 pts. Median treatment duration with panobinostat was 17 days (1–76). Discontinuation from study was due to disease progression in 19 pts (70%) or new leukemia therapy in 1 pt (3%), and it was recorded as due to AE in 5 pts (18%) or to abnormal lab values in 2 pts (7%). CNS new involvement by leukemia occurred in 4 pts. The most common Grade 3/4 AEs were thrombocytopenia in 12 pts (44%) and anemia in 9 pts (33%). Gastrointestinal (GI) AEs were Grade 1/2 for 13 of the 14 events, including diarrhea in 10 pts. 1 pt presented Grade 3 abdominal pain. Atrial fibrillation recorded as possibly related to study drug was the AE cause for discontinuation in 1 pt. Out of 684 records of post baseline ECGs evaluable to date, 1 single QTcF prolongation 〉480 ms was recorded (Grade 2). Notable lab abnormalities were Grade 3 hyperkalemia in 2 pts, Grade 3 hypokalemia in 2 pts, and Grade 3 WBC count increased in 2 pts. Hematologic RTC response was reported for 4 pts, (in Cycle 1 for 1 pt, Cycle 2 for 2 pts, and Cycle 3 for 1 pt). However, these responses were not confirmed. Consistently, no MCyR was observed. No major molecular response was observed from BCR-ABL transcript analysis performed at a central lab from patients blood samples obtained at baseline and post treatment. BCR-ABL mutation analysis by direct sequencing at a central lab showed that in addition to T315I, which was most frequently observed, a spectrum of other mutations were also seen at baseline and at disease progression. Some patients harbored more than one mutation in BCR-ABL at baseline and/or disease progression, which will be presented in details. Single-agent, oral panobinostat at a dose of 20 mg/day, thrice weekly did not show any sustained clinical responses in AP or BC CML patients enrolled. Furthermore, disease progression was very rapidly determined with median therapy duration being less than 3 weeks. This could possibly be related to a too short interval of temporary co-administration of hydroxyurea, as per study protocol. In patients with AP/BC CML resistant to 2 TKIs, oral, single-agent panobinostat at a dose of 20 mg/day, thrice weekly was safe but did not show meaningful clinical activity precluding study continuation. Promising clinical activity of panobinostat has since been observed in various other hematological malignancies, such as CTCL, as well as HL, AML, and MDS — mostly at higher doses. In these and other indications, clinical investigation of the oral and i.v. formulations of panobinostat at different doses and in combination with established standard treatment regimens are planned or ongoing.

Description: Background: MCL is a prognostically unfavorable subtype of B-cell non-Hodgkin’s lymphoma, where autologous stem cell transplant (ASCT) is regarded a standard consolidation of the Ist-line therapy. However most of the pts are elderly or otherwise not illegible for intensive therapy protocols (i.e. only 6 out of 17 MCL patients diagnosed in our Dpt during last 6 months could be subjected to ASCT). Addition of Rituximab to induction chemotherapy increases the response rate, but still most patients subsequently relapse and some kind of consolidation is necessary. Aims: It is postulated, that radioimmunotherapy with 90Y-Zevalin® (90Y-Ibritumomab tiuxetan), could be an efficient consolidation in patients not illegible for ASCT. Methods: In our analysis we included 45 MCL cases subjected to RIT. The first 30 patients were enrolled in the Polish Lymphoma Research Group Trial (PLRG MCL1), a II phase multicenter study, where 90Y-Zevalin consolidated the response after FCM±R. The average follow-up of the study is now over 2 years (13 – 33 months). Further 15 cases with a shorter follow-up, initially treated with FC-R or CHOP - R, are included only in response and toxicity analysis. Only pts responding to initial chemotherapy (

Description: The goal of this study was to pr ove the significance of an early evaluation of leukemic blast reduction based on cytological examination of bone marrow aspirates obtained on day 6 of remission induction treatment. Patients: 152 adult AML patients aged 18–60 (median 47) registered to the PALG prospective trial evaluating the efficacy of 3 remission induction protocols: DAF: daunorubicine (DNR) 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 2h inf. iv d 1–5) DAC (like DAF but cladribin is used at 5 mg/m2 instead of fludarabine) and the standard DA 3+7 regimen. Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) HD AraC. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Bone marrow aspirates were performed before the treatment and on the 6-th day of the first remission induction course, and the MGG stained marrow smears were evaluated at each centre by two experienced hematologists. Results: Based on the proportion of blasts in bone marrow specimen on day 6 patients were arranged into 2 groups: “responders” with 5% of blastic cells in bone marrow (n=31). The complete remission rate (CR) in the “responders” group equaling 86% (82/95) was significantly higher in comparison to that found in the “non responders” group 33%(19/57), p=5% in bone marrow specimens on 6-th day of induction was associated with higher risk of not achieving CR (HR = 51,1; p=0,00002), and with shorter OS (HR=2,9; p=0,004). Conclusion: This prospective, multicenter study demonstrates that a simple and commonly accessible evaluation of the leukemic blasts reduction in bone marrow smear on the 6-th day of remission induction treatment is a reliable and independent predictor for achieving CR and for overall survival. This offers a decision point for an early modification of the treatment strategy.

Description: Cladribine (2-chlorodeoxyadenosine, 2-CdA) has dramatically improved prognosis of hairy cell leukemia (HCL), though the 2-CdA treatment-associated life-threatening infections may shorten potentially long-term survival of HCL patients. In search of optimal mode of 2-CdA administration in HCL, we compared the standard 5-day 2-CdA protocol with a novel weekly 2-CdA schedule that was suggested to be equally effective, but less toxic. Between the 1st January 1998 and the 31st September 2005, 132 patients with previously untreated, active HCL from 14 hematology centers were included to the study. Patients were randomly assigned to receive 2-CdA at 0.12 mg/kg in 2-hour intravenous infusion for 5 days (64 patients), or 2-CdA at 0.12 mg/kg in 2-hour intravenous infusion once a week for 6 weeks (62 patients). The response to chemotherapy was evaluated according to the NCI guidelines and treatment-related toxicity was recorded using standard WHO criteria. One hundred and sixteen patients were included in the final analysis of the trial. Comparison of the treatment response between daily and weekly 2-CdA protocols showed similar complete remission rate (76% and 72%, p=0.86) as well as similar overall response rate (95% and 91%, p=0.41). Survival analysis did not show significant difference between the study arms. Median progression-free survival equaled 4.3 years (95%CI = 3.3 – 5.2) and 5.1 years (95%CI = 4.7 – 5.6) (p=0.28) for patients treated with daily and weekly schedule, respectively. The estimated 6.5 year overall survival was 91% for daily and 88% for weekly 2-CdA protocol, p = 0.40. Interestingly, the analysis of adverse events did not confirm lower toxicity of the weekly 2-CdA schedule. Of special interest, there were no significant differences between daily and weekly protocol in the rate of treatment-related neutropenia (47% vs. 47%, p=0.97), the rate of grade 3/4 infections (18% vs. 26%, p=0.28), or the rate of 2-CdA-related septic deaths (2% vs. 1%, p=0.64). In conclusion, the results of our randomized study indicate that HCL treatment based on weekly 2-CdA infusions for 6 weeks is equally effective, but not safer than standard 5-day 2-CdA protocol.

Description: Cladribine (2-chlorodeoxyadenosine, 2-CdA) treatment-associated infections may shorten potentially long-term survival in hairy cell leukemia (HCL). In search of the optimal mode of 2-CdA administration, 132 patients with untreated HCL were randomized to receive either standard 5-day 2-CdA protocol or a novel schedule of 6 weekly 2-CdA infusions suggested to be less toxic. Analysis of treatment response confirmed similar complete remission rates, overall response rates, progression-free survival, and overall survival in both 2-CdA protocols. However, we did not observe lower toxicity in the weekly schedule. Of special interest, no significant differences were found in the rate of grade 3/4 infections (18% for daily and 26% for weekly protocol, difference −8.2%; 95% confidence interval [CI] −23.2% to 6.9%; P = .28) and the rate of septic deaths (3% for daily and 2% for weekly protocol, difference 1.4%; 95% CI −4.3% to 7.0%; P = .64). In conclusion, HCL treatment with weekly 2-CdA infusions is equally effective but no safer than the standard 5-day 2-CdA protocol.

Description: Abstract 4882 Background: Conventional therapies with cytotoxic agents for disseminated NHL are associated with a high risk of therapy related myeloid neoplasm (tMN). The latency period between exposure to this agents and development of tMN ranges from one to 10 years. Radioimmunotherapy (RIT) uses monoclonal antibodies, specifically binding to antigens of tumor cells, as a carrier for the radioisotope. The radiation is delivered not only to the antibody –bound tumor cell, but also neighboring cells. Methods: In the years 2005–2011 radioimmunotherapy with ibritumomab tiuxetan was used in 102 patients with FL (during consolidation therapy), MCL (as consolidation of the first-line treatment and after achieving PR in the first- or second-line therapy), DLBCL and MCL (in the HDT supported by auto-SCT). 5 patients (4,9%) ( 4 with MCL/ 1 with FL) subjected to RIT developed tMDS. All patients with MCL in previous treatment were exposed to alkylating agents, antymetabolites and inhibitors of II topoisomerase. All patients had hypoplastic bone marrow year after RIT. Results: Median time to diagnosis of tMDS after treatment with RIT was 2,3 years. 4/5 during 6 month transformed into tAML. In peripheral blood of all patients anemia, thrombocytopenia or pancytopenia was observed. All patient in histophatology had dysplastic changes in 3 hematopoetic lines with 5% blast cells, without elevated percentage of ring sideroblasts. Each patient had typical for tMDS complex abnormalities with monosomy of chromosome 5 or 7, or abnormalities of this chromosome [table 1]. Three of this patients was treated with azacitidine, one of this patients was prepared to RIC allo BMT but developed tAML and died during induction therapy. All patients received supportive care. Conclusion: The development of secondary hematological malignancies (tMDS and tAML) after RIT is very closely related to the drugs applied in the induction treatment especially purine analogues. Higher incidence of tMDS in patients with MCL confirm the relationship of occurrence of secondary MDS and AML after radioimmunotherapy with the earlier use of purine analogs (fludarabine) and cumulative damage to bone marrow cells rather than exclusively associated with administration of RIT. Disclosures: No relevant conflicts of interest to declare.