ALBERT

Description: Recent data suggest that tryptase is expressed in neoplastic cells in various myeloid neoplasms. In this study, serum tryptase levels were determined by a fluoroenzyme-immunoassay in 165 healthy subjects, in 925 patients (pts) with hematologic malignancies (myeloproliferative disorders, MPD, n=150; myelodysplastic syndromes, MDS, n=233; acute myeloid leukemia, AML, n=317; acute lymphatic leukemia, ALL, n=26, Non Hodgkin′s lymphomas, NHL, n=30; systemic mastocytosis, SM, n=89), and in a large cohort of control cases (pregnant women, n=11; hepathopathy, n=7; renal failure, n=18; helminth infections, n=29; reactive leukocytosis/thrombocytosis or idiopathic cytopenia, n=115). In healthy subjects, the 95%-percentile ranged between 2.4 and 9.5 ng/ml (median 5.7 ng/ml). Healthy controls aged ≤ 16 years had a slightly lower median serum tryptase level compared to older control subjects (p=0.03). Among pts with non hematologic disorders, slightly elevated serum tryptase levels (up to 24 ng/ml) were detectable in 6/18 pts with severe renal failure and in 3/29 pts with helminth infections. When analyzing hematologic malignancies, tryptase levels 〉15 ng/ml could be detected in pts with myeloid neoplasms exclusively, whereas in most pts with lymphoproliferative disorders, tryptase levels were normal. Among myeloid neoplasms, elevated tryptase levels were recorded in 83% of the pts with SM, 36% of pts with AML, 34% of the pts with CML, and 29% of the pts with MDS. The highest tryptase levels, sometimes exceeding 1000 ng/ml, were found in pts with SM or AML-M4eo. In pts with CML, elevated tryptase levels were found to be associated with an unfavorable prognosis concerning survival (survival in CML pts with tryptase 15 ng/ml, after 60 months, p

Description: Synthesis of histamine in hematopoietic progenitor cells may be one of the earliest events in mast cell-development from pluripotent hematopoietic progenitor cells. In the present study, we asked whether the key enzyme involved in histamine generation, histidine decarboxylase (HDC), can be employed as an immunohistochemical marker for the detection of (neoplastic) mast cells (MC) in patients with cutaneous (CM) or systemic mastocytosis (SM). To address this question, we examined bone marrow biopsy specimens in a cohort of 101 patients (CM, n=10; indolent SM, n=46; SM with associated clonal non-MC lineage disease, n=31; aggressive SM, n=10; MC leukemia, n=3; MC sarcoma, n=1) using an antibody against HDC. Independent of the maturation stage of MC or subtype of disease, the anti-HDC antibody produced clear diagnostic staining results in all patients with bone marrow involvement examined including those with MC leukemia and MC sarcoma, in which MC are particularly immature and often escape analysis when examined by conventional stains. In these patients (MC leukemia, n=2; MC sarcoma, n=1), expression of HDC was reconfirmed at the mRNA level by RT-PCR analysis performed with RNA of highly enriched sorted CD117+ MC. In patients with CM or normal/reactive bone marrow (n=30), no HDC-positive infiltrates were detected. In these patients, only a few hematopoietic cells, presumably basophils, were found to react with the anti-HDC antibody. In summary, HDC is expressed in neoplastic bone marrow MC in patients with SM independent of the maturation stage of cells or the variant of disease. HDC should therefore be considered as a new MC marker in the screen panel of antigens employed to diagnose high grade MC malignancies.

Description: Introduction:CD38 is a type II transmembrane glycoprotein widely expressed in many hematological malignancies including multiple myeloma (MM). MOR202, a HuCAL-derived, human IgG1 CD38 monoclonal antibody, induces antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). MOR202 does not induce complement-dependent cytotoxicity, which is suspected to be a major contributor to infusion-related reactions (IRRs). Preclinical models of MM demonstrate high single-agent antitumor activity of MOR202 and synergy in combination with immunomodulatory drugs (IMiDs), lenalidomide (LEN) or pomalidomide (POM). Methods: This is an interim analysis of a multicenter, dose-escalation phase I/IIa study of MOR202 in relapsed or refractory (RR)MM. Preliminary safety and efficacy data from 3 patient cohorts treated with clinically relevant doses of MOR202 (administered as an IV 2-hour infusion), alone or in combination with an IMiD are presented: MOR202 4, 8 and 16 mg/kg weekly; MOR202 8 or 16 mg/kg weekly with either LEN or POM. All patients in these cohorts also received low dose dexamethasone. Primary objectives were to evaluate the safety, maximum tolerated dose (MTD) and recommended phase II dose of MOR202. Secondary objectives included an assessment of overall response rate, duration of response and progression-free survival. Results: As of July 12, 2016, a total of 66 patients had been treated; 31 in clinically relevant cohorts, including 18 patients receiving MOR202 alone, 8 receiving MOR202 + LEN and 5 receiving MOR202 + POM. Patients treated with MOR202 alone and MOR202 + POM had both received a median of 4 prior lines of therapy; 78% and 100% had been refractory to last prior treatment, respectively. Patients treated with MOR202 + LEN had received a median of 2 prior lines of therapy and 50% had been refractory to last prior treatment. Most of the patients had received bortezomib, LEN, cyclophosphamide, and melphalan alone or in combination with autologous stem cell transplant as part of their prior regimens. In this trial the MTD has not been reached yet. MOR202 alone or in combination with an IMiD was well tolerated, with mainly hematological toxicity reported. A 2-hour MOR202 infusion was feasible in all patients. In the clinically relevant cohorts only 1 patient discontinued due to an adverse event considered to be related to MOR202 (platelet count decreased) and no deaths related to any of the study drugs occurred. IRRs were seen in only 3/31 (10%) patients, all occurring during the first infusion. All IRRS were ≤ grade 2. So far, 28 patients were evaluable for response in the MOR202 clinically relevant cohorts. Of 16 evaluable patients in the MOR202 alone cohort, 3 partial responses (19%) and 2 very good partial responses (13%) were reported. In the MOR202 + LEN cohort 5/7 partial responses were seen, and 3/5 patients responded to MOR202 + POM treatment including 2 complete responses. Median time to response was 4 weeks, with responses tending to deepen over time. Most responses (10/13) are ongoing with the longest duration of response currently being 48 weeks. Preliminary analysis in 5 patients revealed preservation of high CD38 levels on MM cells under MOR202 therapy, with a mean decrease of only 10% from baseline to day 1 cycle 2 (4 weeks). Conclusions: In this analysis, a 2-hour infusion of MOR202 (up to 16 mg/kg) alone, or in combination with POM or LEN showed a very good safety profile, particularly an excellent infusion tolerability in heavily pretreated patients with RRMM. Promising preliminary efficacy and long-lasting tumor control was seen for MOR202 +/- IMiDs. The data suggest that CD38 expression on patient MM cells is preserved during treatment. Disclosures Raab: Novartis: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy, Research Funding. Goldschmidt:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Agis:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau. Engelhardt:Amgen: Research Funding; Janssen: Research Funding; MSD: Research Funding; Celgene: Research Funding. Ferstl:Novartis: Other: Case report presentation; Bristol Myers Squibb: Other: Advisory Board. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Onyx: Consultancy; BMS: Consultancy, Honoraria; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Jarutat:MorphoSys AG: Employment. Weinelt:MorphoSys: Employment. Endell:MorphoSys AG: Employment, Patents & Royalties. Boxhammer:MorphoSys AG: Employment, Patents & Royalties. Peschel:MophoSys: Honoraria.

Description: Basophils are highly specialized granulocytes that express a unique profile of antigens and increase in myeloproliferative disorders. In chronic myeloid leukemia (CML), basophilia is an independent prognostic variable. So far, however, no reliable immunohistochemical approach for routine-detection and enumeration of bone marrow (bm) basophils has become available. To overcome this disadvantage, we have applied the anti-basophil antibody 2D7 on formalin-fixed, paraffin-embedded sections of normal bm and bm from patients (pts) with chronic myeloid leukemia (CML; chronic phase, n=21; accelerated phase, n=9), other myeloproliferative disorders (idiopathic myelofibrosis [IMF], n=3; polycythemia vera [PV], n=7; essential thrombocythemia [ET], n=7), and normal / reactive bm (n=32). As assessed by serial section-staining of bm specimens, the 2D7 antibody was found to be a basophil-specific immunohistochemical reagent. In serial bm sections, 2D7+ basophils co-expressed histidine decarboxylase, CD15, and CD43, but did not express B- or T-cell restricted antigens corresponding to the phenotype of normal blood basophils. Bm basophils were found to increase in number in pts with CML and other myeloproliferative disorders compared to normal bm (median 2D7+ cells/mm2 bm: normal bm: 7; CML: 46; IMF: 26; PV: 21; ET: 21, p

Description: Tryptases are serine proteases primarily expressed in mast cells. Normal blood basophils express only trace amounts of the enzyme. However, recent immunohistochemical studies have raised the possibility that neoplastic basophils express significant amounts of tryptase. In this study, tryptase expression was analyzed in normal and neoplastic basophils by immunoelectron microscopy using antitryptase monoclonal antibody G3. Basophils were obtained from patients with chronic myeloid leukemia (CML), idiopathic myelofibrosis (IMF), and myelodysplastic syndrome (MDS), and from healthy donors. Tryptase-immunoreactive material was detected in cytoplasmic granules of basophils in CML, IMF, and MDS. By contrast, normal basophils did not contain significant amounts of tryptase by immunoelectron microscopy. As assessed by reverse transcription-polymerase chain reaction, neoplastic basophils contained messenger RNA (mRNA) for α-tryptase, but no β-tryptase mRNA. In summary, these data provide evidence that neoplastic basophils in CML, IMF, and MDS can express detectable amounts of tryptase. Therefore, tryptase should not be regarded as specific for mast cells when neoplastic myeloid cells are analyzed.

Description: Abstract 3382 Siglec-3 (CD33) is an established therapeutic target in acute myeloid leukemia (AML). We and others have shown that CD33 is expressed on immature CD34+/CD38- stem cells in AML. We here report that leukemic stem cells obtained from patients with chronic myeloid leukemia (CML) display high levels of CD33, and that CD33 may serve as a potential target in CML. As assessed by multi-color flow cytometry, CD34+/CD38-/CD123+ CML progenitor cells in chronic phase (CP) were found to express significantly higher levels of CD33 compared to normal CD34+/CD38- bone marrow stem cells (figure). By contrast, similar levels of the cell surface antigen MDR1 (CD243) were detected when comparing normal and CML progenitors. In chronic phase (CP) CML, CD33 was found to be expressed homogeneously on most or all CD34+/CD38- stem cells. In patients with accelerated (AP) or myeloid blast phase (BP), CML stem cells also co-expressed CD33, but the levels of CD33 varied from donor to donor, and in one patient, most CML stem cells appeared to be CD33-negative cells. In two patients with CML, CD34+/CD38- cells were highly enriched by cell sorting (purity 〉98%) and found to contain CD33 mRNA in qPCR analysis. The presence of BCR/ABL and thus the leukemic origin of these cells was confirmed by FISH analysis and PCR. We then examined the effects of the CD33-targeted drug gemtuzumab/ozogamicin (GO) on growth of primary CML cells. As assessed by 3H-thymidine uptake, GO produced growth inhibition in leukemic cells in all patients tested (CP, n=13; AP, n=3). The effects of GO on leukemic cell growth were dose-dependent and occurred at relatively low concentrations, with IC50 values ranging between 1 and 100 ng/ml. GO effects were also seen in precursor-enriched Lin-negative CML cells (n=3). As assessed by Annexin-V staining, GO was found to induce apoptosis in CD34+/CD38- CML progenitor cells. Next we investigated drug combination effects. In these experiments, GO was found to synergize with nilotinib and bosutinib in producing growth inhibition in primary CML cells. In conclusion, CD33 is expressed abundantly on immature CD34+/CD38- progenitor cells in CML. Whether GO can be employed to eradicate residual leukemic stem cells in CML patients alone or in combination with BCR/ABL kinase inhibitors remains at present unknown. Figure: Expression of CD33 on CD34+/CD38- cells in normal bone marrow (n=7) and patients with CML in chronic phase (CP, n=16) or advanced phase (AP/BP, n=11) of the disease. Figure:. Expression of CD33 on CD34+/CD38- cells in normal bone marrow (n=7) and patients with CML in chronic phase (CP, n=16) or advanced phase (AP/BP, n=11) of the disease. Disclosures: Valent: Novartis: Research Funding; Bristol-Myers Squibb: Research Funding.

Description: Introduction: Renal impairment (RI) is frequent in patients with Multiple Myeloma (MM) and is a proven negative prognostic factor for overall survival (OS). MM patients with impaired renal function often fail to qualify for high-dose chemotherapy and are excluded from autologous stem cell transplantation (ASCT), since a higher transplant-related mortality has been postulated. However, it remains unclear whether these historical inferior outcome data still hold true in times of modern immuno-chemotherapeutical therapy regimen. Further, nephrologic definition criteria for renal impairment have evolved as well and have not yet been fully introduced into MM patient care. We thus aimed at evaluating outcome data of MM patients undergoing ASCT after immuno-chemotherapy applying current nephrologic standard criteria for RI. Methods: MM patients who had undergone ASCT at our center between 1999 and 2015 were included. Renal function was determined and staged both at the time of diagnosis and transplantation by estimated glomerular filtration rate (eGFR according to the MDRD formula).RI was defined as eGFR

Description: BACKGROUND: Treatment options in patients with RRMM who are refractory to bortezomib (BORT) and lenalidomide (LEN) are limited. POM/LoDEX is approved in patients with RRMM after ≥2 prior treatment regimens (including both BORT and LEN), who relapsed on the last line of therapy. The aim of this ongoing, multi-center, non-interventional study is to prospectively collect real world data in RRMM patients treated with POM/LoDEX in an Austrian clinical routine setting. PATIENTS & METHODS: Adult patients with RRMM who had received ≥2 prior antimyeloma treatments (including LEN and BORT) who experienced disease progression on the previous line of therapy were enrolled and treated with POM/LoDEX until disease progression or unacceptable toxicity. Emphasis was put on the collection of safety data (adverse events [AEs]) and of efficacy data (objective response rate [ORR; ≥partial response, PR]; progression-free survival [PFS]). A source data verification level of 75% was reached in 74% of patients. Descriptive statistics were used to summarize the data. RESULTS: From 09/2014 to 06/2018, 63 patients were enrolled by 9 Austrian centers; 61 of them were eligible for analysis. At inclusion, the median age was 69 years (range 44-90); 15 patients (25%) were older than 75 years; 37 patients (61%) were male. Most patients (96%) had an ECOG performance status of ≤2. ISS stages were evenly distributed (I: 39%; II: 25%; III: 30%). The median number of prior lines of therapy was 4 (range 1-10). Prior treatments of almost all patients included an immunomodulatory drug (98%) and a proteasome inhibitor (97%). Half of the patients (49%) underwent a prior stem cell transplantation. The most frequent starting dose of POM was 4 mg per day (82%); 43% of the patients received the full LoDEX dose of 40 mg weekly. The median number of POM treatment cycles was 10 (range 1-63). At cycle 10, 81% of patients still received POM at a dose of 4 mg, while only 19% still received LoDEX at the full dose of 40 mg. The median PFS for 49 evaluable patients was 11.8 months. Response information was available for 46 patients. The ORR with POM/LoDEX was 50%. Seven patients (15%) achieved a complete response (CR), 5 patients (11%) a very good PR, and 11 patients (24%) a PR; 4 patients still have an ongoing response. A total of 23 patients (38%) received at least one additional antimyeloma agent at any time (57% started upfront; 43% delayed onset) during their treatment with POM/LoDEX. The ORR in this subgroup (n=16) was 63%. The median PFS and ORR stratified by application of a third or further antimyeloma agent are shown in Table 1. Safety information was available for 47 patients (77%), 250 AEs were documented; of those, 94 (38%) were drug-related. Most AEs were non-serious (78%); 18% required hospitalization, 2% (not drug related) were fatal. The most common AEs were infections (22%) and neutropenia (9%). The most common reasons for treatment discontinuation were tumor progression (n=36, 59%), and death (n=4, 7%); one patient (2%) discontinued treatment due to toxicity. At the time of data cutoff, 13 patients (21%) were still on treatment. CONCLUSION: This interim analysis of real-world data demonstrates that POM/LoDEX is an effective and safe treatment in patients with RRMM. Presented response data (PFS: 11.8 months; ORR: 50%) are somewhat better compared to data from earlier, randomized trials (MM-003, NCT01311687). Despite the limitations of a non-interventional study approach, these encouraging findings may also be a consequence of the increased practical experience clinicians have with POM/LoDEX today. In contrast to LoDEX, dose reductions of POM are rare, underlining its good tolerability. As indicated by an increase of the ORR from 43 to 63% (subgroup analysis), efficacy of POM/LoDEX may be enhanced by addition of a third antimyeloma agent. Disclosures Lechner: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Greil:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hartmann:Novartis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Celgene: Research Funding. Krauth:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Gisslinger:AOP Orphan: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Shire: Honoraria; Takeda: Consultancy, Honoraria. Vogl:BMS: Consultancy, Honoraria; Eisei: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Janssen: Honoraria; Pfizer: Consultancy, Honoraria; Eli-Lilly: Consultancy, Honoraria; Celgene: Honoraria; Merck: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Honoraria; Astellas: Honoraria; Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Ohler:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greinix:Celgene: Consultancy; Amgen: Consultancy, Speakers Bureau; Therakos: Speakers Bureau; Roche: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Sormann:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Andel:Roche: Research Funding, Speakers Bureau; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Rechberger:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Agis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Prothena: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Description: Background: CD38 is a type II transmembrane glycoprotein widely expressed in many hematological malignancies including multiple myeloma. MOR202, a human IgG1 CD38 monoclonal antibody demonstrates cytotoxic activity. The main mode of action for MOR202-induced cell lysis is through antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis. MOR202 does not induce complement-dependent cytotoxicity, a suspected major contributor to infusion-related reactions (IRRs) observed with other monoclonal antibodies. MOR202 has demonstrated activity as monotherapy and synergy in combination with the immunomodulatory drugs lenalidomide (LEN) and pomalidomide (POM) in preclinical models of multiple myeloma. Methods: The primary objectives of this multicenter, dose-escalation phase I/IIa study in patients with RRMM (NCT01421186) are to evaluate the safety, and to determine the maximum tolerated dose (MTD)/recommended phase II dose of MOR202. We present the primary analysis of safety and efficacy data from patient cohorts treated with MOR202 at doses of 4, 8 and 16 mg/kg q1w plus Dex (≤40 mg), or MOR202 at 8 or 16 mg/kg q1w plus LEN/Dex or POM/Dex. MOR202 infusion time was 2 hours for all three regimens, which was successfully reduced to 30 minutes for the majority of patients at the time of primary analysis (cutoff 31 Dec 2017). Results: As of 31 December 2017, 91 patients had been treated, 56 at the doses previously described: 18 patients were treated with MOR202 + Dex, 17 with MOR202 + LEN/Dex and 21 with MOR202 + POM/Dex. Before entering the study, patients had undergone a median of 3, 2 and 3 prior treatment lines, respectively. Notably all patients in the MOR202 + POM/Dex group were refractory to lenalidomide. The MTD of MOR202 was not reached. The combinations were generally well tolerated. In the 56 patients, grade ≥3 adverse events (AEs) were mainly hematological in nature. Two patients discontinued due to a MOR202-related AE (one a grade 4 thrombocytopenia and one a grade 3 bacterial infection complicated by acute kidney failure). IRRs to MOR202 (all grade 1 or 2) were observed in 4/56 (7%) patients. These mainly occurred during the first infusion. Twelve of 16 patients remaining on study at the time of primary completion received MOR202 as a 30 minute infusion without obvious safety concerns. In patients treated with MOR202 + Dex, 28% (5/18) showed a response: 3 partial responses (PRs) and 2 very good PRs (VGPRs). Higher response rates of 65% and 48% were observed in patients treated with MOR202 + LEN/Dex (11/17, 7 PRs, 2 VGPRs, 2 complete responses [CRs]) and MOR202 + POM/Dex (10/21, 5 PRs, 3 VGPRs and 2 CRs) respectively. Median time on study was 3.8 months for patients treated with MOR202 + Dex, 9 months for patients who received MOR202 + LEN/Dex and 4.7 months for those treated with MOR202 + POM/Dex. Longest response duration was 27.6 months (MOR202 + POM/Dex). Median progression-free survival was 8.4 months in patients treated with MOR202 + Dex, was not reached in those receiving MOR202 + LEN/Dex and was 17.5 months in those receiving MOR202 + POM/Dex. Conclusions: MOR202 administered as infusions as short as 30 minutes at doses up to 16 mg/kg with Dex or in combination with LEN/Dex or POM/Dex in heavily pretreated patients with RRMM showed a favorable safety profile, including good infusion tolerability. Promising efficacy and long-lasting tumor control were observed for MOR202 + Dex and in particular for MOR202 combined with LEN/Dex or POM/Dex. Disclosures Raab: Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Goldschmidt:Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy. Agis:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Prothena: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Ferstl:Janssen Cilag: Honoraria, Other: Travel EHA. Gramatzki:Affimed: Research Funding. Rollig:Bayer: Research Funding; Janssen: Research Funding. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jarutat:Morphosys AG: Employment. Weinelt:Morphosys AG: Employment. Winderlich:Morphosys AG: Employment. Peschel:Morphosys AG: Honoraria.

Description: Abstract 4263 Chronic myeloid leukemia (CML) is a stem cell (SC) disease defined by the BCR/ABL oncoprotein that is considered essential for abnormal growth and accumulation of neoplastic cells. Based on in vitro studies and mathematical models, CML clones are considered to be organized hierarchically similar to normal hematopoiesis. More recent data suggest, that CML cells grow in subclones that usually exhibit SC function but vary in their leukemia-initiating potential. The situation is even more complex in patients treated with TKI. In these patients, intrinsic as well as acquired resistance against TKI have been described and recognized as an emerging problem and challenge in practice and research. Most SC concepts focus on imatinib-resistant mutants of BCR/ABL, that are detectable in subclones. However, several questions and phenomena that occur in TKI-treated patients remain to be solved. Based on laboratory and clinical observations, we propose the existence of 6 distinct phases of CML SC development (SCD): a) a Ph-negative phase, b) an early Ph-positive preleukemic SCD-phase in which subclones are (very) small and usually undetectable, c) a pre/leukemic SCD-phase in which one or more subclones expand(s) and replace(s) normal myelopoiesis but still produce(s) normal WBC, d) chronic phase (CP), e) accelerated phase (AP), and f) a blast phase (BP). The latency period until progression into a next SCD phase is variable and may depend on several different factors including subclone inhibition by chalones like lipocalin and other factors, different growth kinetics produced by various BCR/ABL mutants, and TKI-induced subclone-selection. Phase a) may explain the rare occurrence of Ph-negative subclones (+OCA) during TKI treatment. Phase b) may explain why BCR/ABL mutants are not detectable before TKI therapy is initiated, why mutant- and ACA subclones “appear” in CCyR patients after a certain latency period, and why one patient can develop two or more BCR/ABL mutants in different subclones. Phase b) may also explain the rare detection of very small quantities of BCR/ABL in healthy individuals and constant low level-MRD in a few CML patients in whom therapy was stopped. Phase c) can explain early CML patients in whom WBC are normal in repeated tests; and explain relapsed TKI-resistant patients in whom under TKI therapy normal hematopoiesis is replaced by the mutant subclone but WBC remain normal for weeks to several months. The SCD phases a) through c) are not accessible in any of the conventional xenotransplant models available. Even in SCD phases d) through f), it is quite difficult to demonstrate stable long term engraftment in xenotransplant mouse models, although stem cell subclones obtained from patients in f) may grow in NOG- or NSG mice similar to AML SC. However, even if this may be a reproducible approach, analysis of all relevant subclones in these patients will probably not be achievable unless additional oncogenes are introduced in these subclones. In summary, our new concept extends the hydra model of cancer stem cell development for CML by introducing a step wise progression-model with 6 defined phases of SCD. This model may have theoretical and clinical implications for patients with freshly diagnosed and TKI-resistant CML and for cancer stem cell research in general. Disclosures: No relevant conflicts of interest to declare.