ALBERT

Description: Introduction The oral BTK inhibitor ibrutinib was recently approved for frontline CLL therapy based on RESONATE-2, which included only patients (pts) age ≥65 (Burger et al., 2016). In the absence of comparative data, FCR remains a standard initial therapy for younger CLL pts, particularly in light of recent data suggesting that mutated IGHV predicts long disease free survival after FCR (Thompson et al., 2016, Fischer et al., 2016). However, pts with higher risk CLL such as del(17p) and unmutated IGHVhave less durable responses. Moreover, only about 20% of CLL pts will achieve complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) with frontline FCR (Boettcher et al., 2012). Given the favorable toxicity profile and substantial efficacy of ibrutinib across CLL risk types, we developed an investigator-initiated, multicenter phase II study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL pts (NCT02251548). Methods The primary objective is to determine the rate of CR with BM MRD-neg in younger CLL pts treated upfront with iFCR. Secondary endpoints include response rate, PFS, and safety/tolerability. Ibrutinib 420 mg daily monotherapy is started 7 days prior to FCR, which is given at standard doses together with ibrutinib for up to 6 cycles. Responders continue on ibrutinib maintenance until progression or unacceptable toxicity. Growth factor support and antimicrobial prophylaxis are mandatory. Eligibility criteria include: age ≤ 65, requiring initial treatment by IW-CLL criteria, ECOG PS ≤1, and adequate organ function. CTCAE v4 and IW-CLL criteria are used to evaluate toxicity and efficacy, with response evaluations after 3 cycles, 2 mos. after final FCR (primary endpoint evaluation), and q6 mos. thereafter. MRD is assessed by 4-color flow cytometry (10-4sensitivity). Results As of August 1, 2016, the study reached full accrual at 35 pts. The median age at enrollment was 55 yrs (range 38-65). 9/33 tested (27%) had del(11q) and 4/33 tested (12%) had del(17p). Unmutated IGHV was present in 20/31 tested (65%), ZAP-70 was positive in 21/32 tested (66%), TP53 mutation was present in 2/31 tested (6%), and NOTCH1 mutation was present in 2/21 tested (10%). We initially enrolled 10 pts in a safety lead-in cohort and did not see any unexpected toxicities. In the entire cohort of 35 pts, hematologic toxicity included grade (gr) 4 neutropenia in 1 pt (3%), as well as gr 3 neutropenia (15%), thrombocytopenia (18%), and anemia (6%). All grade non-hematologic toxicities occurring in 〉15% of pts included nausea (68%), bruising (35%), fatigue (29%), and rash (21%) (all gr 1/2) and diarrhea (21%) (all gr 1). The only bleeding events were gr 1 epistaxis in 2 pts. SAEs included gr 4 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumonia, and gr 3 appendicitis in 1 pt each. 9% of pts experienced ≥gr 3 infection. A median of 6 cycles of FCR were given (range 3-6). One pt had ibrutinib dose reduction (pt with febrile neutropenia), and 18% of pts had at least 1 dose reduction of chemotherapy. Twenty-eight pts have undergone primary endpoint re-staging after completing the iFCR combination and 26 pts have been tested for BM MRD. In these 26 pts, the rate of CR with BM MRD-neg is 39% (10/26). In the 28 pts with re-staging, the ORR is 100%, including 39% (11/28) with CR or CRi. 17/28 (61%) pts had a PR, and all 17 PR pts have residual lymph nodes ≤ 2.5 cm in long axis by CT imaging. BM was MRD-neg in 23/26 tested (89%), including 13/17 (76%) of pts in PR. With a median follow-up of 12.1 months (range 0.1-21.1), all pts are alive, and 33 of the 35 pts remain on treatment. One pt who completed 6 cycles of iFCR and achieved CR with BM MRD-neg declined ibrutinib maintenance and remains in MRD-neg CR at 10 months off therapy, and one pt with del(17p) achieved MRD-pos PR and elected to pursue allogeneic stem cell transplant. Conclusions iFCR induces deep responses in previously untreated young CLL pts, with 39% of evaluable pts achieving CR with BM-MRD-neg and 89% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities were observed, possibly due to mandatory use of growth factor support and antimicrobial prophylaxis. 76% of PR pts have achieved BM MRD-neg, and all of these pts have small residual lymph nodes. Pts continue on ibrutinib maintenance and will be monitored for conversion to CR with BM MRD-neg. over time. Disclosures Davids: Genentech: Consultancy, Honoraria, Research Funding; Infinity: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Abramson:Gilead: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Consultancy. Fisher:Pharmacyclics: Consultancy. Brown:Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy.

Description: Background: In 1994 Severe Chronic Neutropenia International Registry (SCNIR) opened for enrollment of patients with at least 3 absolute neutrophil counts (ANC) less than 0.5 x 109/L during a three month period. At that time severe chronic neutropenia (SCN) was categorized as cyclic, congenital, autoimmune or idiopathic based largely on clinical criteria. A randomized trial had established effectiveness of treatment with granulocyte colony-stimulating factor (G-CSF), but long-term consequences of such treatment were unknown. Hypothesis: We began the SCNIR based on the hypothesis that underlying pathophysiology, natural history of patients with chronic neutropenia and benefits and risk of G-CSF therapy could only be accurately established through an international registry with long term follow-up of patients with these rare hematological disorders. Methods: SCNIR enrollment requires informed consent, ANC90%) of severe outcomes (e.g. MDS/AML, failure to respond to G-CSF, death from infections, need for stem cell transplant) often many years after SCNIR enrollment and beginning G-CSF therapy. GSD1 patients improve with G-CSF treatment, but experience splenomegaly and continued problems with infections or complications. The SCNIR through a SDS sub-registry is redefining Shwachman-Diamond syndrome; only about one-half of enrollees have “classic” presentation and a substantial number with “classic presentation” lack mutations in SBDS. The SCNIR is participating in an NIH trial of a CXCR4 antagonist for treatment of WHIM syndrome, as an example of molecularly targeted treatment for this rare disease. The SCNIR is also the key resource for discovery of genetic causes for congenital neutropenia, e.g., G6PC3, HAX1, and TCIRG1 and others, recognition of differences in frequency of autosomal dominant and recessive SCN in populations of Europe and North America and identifying congenital neutropenia cases of unknown cause. Genetic testing has also broadened the clinical spectrum of these disorders. Conclusions: Through the efforts of patients, families, physicians, nurses and investigators, and with support from the NIH, industry, and private philanthropy, chronic neutropenia is now far better understood at the genetic, molecular and cellular level than 20 years ago. Treatment responses to G-CSF are well characterized; novel therapies are emerging; and the prognosis for patients with SCN appears to be improving. The knowledge gained through the SCNIR and availability of G-CSF has redefined clinicians’ approach to chronic neutropenia. The SCNIR is a model of international research collaboration to understand rare diseases in hematology and other areas of medicine. Broad enrollment criteria, physician, patient and family participation, a dedicated staff, and continuing cooperation underlie success of the SCNIR and this model to understanding rare diseases. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding. Boxer:Amgen: Equity Ownership. Morrow:Amgen: Employment.

Description: Background: Since 1994 the Severe Chronic Neutropenia International Registry (SCNIR) has enrolled children and adults with 〉 3 absolute neutrophil counts (ANCs) 〈 0.5 x 109/L during a 3 month period to understand the pathobiology, natural history and treatment responses for severe chronic neutropenia. We have previously reported on the frequency and risk of myelodysplasia (MDS) and acute myeloid leukemia (AML) in patients with congenital neutropenia. For this report we reviewed patterns of hematological complications and malignancies occurring in all patients enrolled through the North American office of the SCNIR. Methods: Enrollment required informed consent, and patients and their physicians provided demographic, clinical and laboratory data including bone marrow results. Genetic testing was not required. Patients were followed with annual reports on blood counts, infections, malignancies and hospitalizations. Results: From 1994 to 2018 the Seattle SCNIR office has enrolled 1672 patients in the following categories: congenital 637 (38%), cyclic 259 (15%), and idiopathic / autoimmune 776 (47%), and many have been followed now for more than 15 years. There are approximately 17,577 person years of the observational data in this Registry. The congenital category now includes patients with mutations in ELANE, SBDS, TAZ, COH1, CXCR4, SLC37A4, G6PC3, WAS, CSF3R, SRP54, GFI1, VPS45, JAGN1, HAX1 and also patients with severe neutropenia from an early date in childhood without a genetic diagnosis. Cyclic neutropenia patients have demonstrated oscillations in ANC. The idiopathic and autoimmune category includes children and adults including some with large granular lymphocytes (LGL) syndrome without recognized features of a lymphoproliferative disorder. Most patients in all categories have been treated with granulocyte colony-stimulating factor (G-CSF). Findings: MDS or AML has occurred in 70 of the 1672 patients; 99% have clinical diagnosis of a hereditary type of neutropenia: severe congenital neutropenia (55), glycogen storage disease 1b (3), congenital immunodeficiency (2), Shwachman-Diamond syndrome (SDS) (5), WHIM syndrome (1),Wiskott-Aldrich syndrome (2), cyclic neutropenia (1) and idiopathic neutropenia (1). The median age at diagnosis of AML/MDS was 15.3 years (mean 18.3, +/- 1.79 SEM [range 0.40 - 70.6]); 69 of 70 were treated with G-CSF, median dose = 7.1 mcg/kg/day (mean 7.3, +/- 1.3 SEM )(range 0.18 - 100). One Shwachman-Diamond patient never received G-CSF. Outcomes for AML/MDS patients receiving chemotherapy with HSCT before 2000 were poor with 3/17 (18%) survivors. Since 2000 there were 35/53 (66%) survivors. Five patients developed myelofibrosis (4 congenital and 1 idiopathic). Two of the congenital patients later developed AML (1 living after treatment with a HSCT, 1 deceased). The clinical diagnosis of cyclic neutropenia has a favorable prognosis with G-CSF treatment, with only one probable case in 3,833 person years of clinical observation. 1 Twelve patients developed T-cell lymphoproliferative disorder (1 autoimmune neutropenia, 3 congenital neutropenia, 8 idiopathic neutropenia (4 with LGL features)). Five of these patients are living, all in the idiopathic group, 3 of 5 living patients have features of the LGL syndrome. Ten patients have reported other hematological malignancies; CML in a congenital patient after treatment with HSCT (living), CLL in a cyclic patient (living), CMML in an idiopathic patient after treatment with a HSCT (deceased). Six of the 10 patients have developed lymphoma; cyclic neutropenia (1), idiopathic/autoimmune neutropenia (5). Only one SDS patient has developed aplastic anemia. Other cancers/non-hematological malignancies have occured mostly in older patients: breast cancer (15) colon cancer (6), dermatological malignancies (13), hepatoma (1), lung cancer (1), prostate cancer (1), thyroid cancer (1). Conclusions: The hematological consequences of severe chronic neutropenia depend on the underlying etiology. MDS and AML occur largely in patients with the congenital or hereditary neutropenias. The diagnosis of cyclic neutropenia and chronic idiopathic / autoimmune neutropenia portends a favorable prognosis, based on a total of 10482 person years of observation. Marrow failure and aplastic anemia are not expected consequences of severe chronic neutropenia. Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Newburger:X4 Pharmaceutics: Consultancy, Honoraria; TransCytos LLC: Consultancy; Janssen Research & Development, LLC: Consultancy, Honoraria.

Description: Backgound Venetoclax (V) plus obinutuzumab (O) regimen is active as frontline CLL treatment; a little over half of patients (pts) will achieve undetectable minimal residual disease in the bone marrow (BM-uMRD) with one year of time-limited therapy (Fischer et al. NEJM 2019). Novel strategies may further augment the efficacy of VO. Ibrutinib was previously combined with VO, but relatively high rates of infusion reactions and neutropenia were observed, as were the characteristic toxicities of ibrutinib including diarrhea and bruising (Rogers et al. Blood 2018). Acalabrutinib (A), a more selective BTK inhibitor, is well-tolerated and active as monotherapy or with O, and we previously found that it sensitizes CLL cells to V (Deng et al. Leukemia 2017). We hypothesized that a time-limited triplet combination of A, V, and O (AVO) could achieve a high rate of BM-uMRD with good tolerability. For the first time we now report on the safety and preliminary efficacy data of AVO in previously untreated CLL pts. Methods This ongoing open-label, single arm, phase 2 investigator-initiated study (NCT03580928) enrolled pts with previously untreated CLL without restriction by prognostic marker status. Eligibility: requiring treatment by iwCLL criteria, ECOG PS ≤ 2, creatinine clearance ≥50ml/min, absolute neutrophil count ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially (see figure), with one 28-day cycle lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then V ramp-up beginning at C4, followed by 3 more cycles of triplet AVO therapy. After 6 months of O, the AV doublet continues through C15; pts with BM-uMRD-negative CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue therapy if in BM-uMRD CR at that time. Response is assessed by 2018 iwCLL criteria, including bone marrow biopsy with MRD testing in the BM and peripheral blood (PB) by 8-color flow cytometry at a sensitivity of at least 10-4. The primary endpoint is the rate of BM-uMRD CR after 15 cycles. Non-hematologic adverse events (AEs) are assessed by CTCAE v5.0, with hematologic toxicity determined by iwCLL criteria. Results The data cut for this interim analysis was July 11, 2019. The study is fully accrued at 37 pts. Median age: 63 years (range: 41-78), 73% male. Baseline prognostic features: unmutated IGHV in 23 (62%) pts, TP53 aberrant disease (defined as either del(17p) and/or TP53 mutation) in 10 (27%) pts, del(11q) in 10 (27%) pts, and complex karyotype in 7 (19%) pts. Thirty-six pts remain on study drugs with a median time on therapy of 8 months (range: 2-11). One pt withdrew consent after 6 cycles due to gastrointestinal symptoms. The overall response rate for the 24 pts who have completed re-staging at C8 is 100%, 18 (75%) PR and 5 (25%) CR. At C8 restaging, 65% of pts were PB-uMRD, 50% of pts were BM-uMRD, and 3 pts (13%) had BM-uMRD CRs. In 8 pts with TP53-aberrant disease who have reached C8, 6 had PR and 2 had CR, with 3 pts BM-uMRD. The most frequent AEs have been fatigue (81% total, 78% gr 1+2, 3% gr ≥3) and headache (76% total, 73% gr 1+2, 3% gr ≥3). Bruising was reported by 16 pts (43%, all gr 1+2). The most frequent gr 3/4 AE has been neutropenia (68% total, 32% gr ≥3). Infusion-related reactions were seen in 8 pts (22%, 19% gr 1+2, 3% gr ≥3). Laboratory tumor lysis syndrome (TLS) occurred in 2 pts (5%), both gr 3 immediately after starting O and prior to any V; both pts continued O. Out of 32 pts, 31 (97%) were medium-to-high risk for TLS on C1D1 but only 3 (9%) were medium-to-high risk at V initiation on C4D1, with 4 medium-to-low risk pts electively admitted for V initiation. One case of gr 3 atrial fibrillation and no cases of hemorrhage or febrile neutropenia were observed. Conclusion Our preliminary data suggest that even at an early response evaluation after 8 cycles of therapy (including only 4 months of V), AVO as frontline CLL therapy leads to a high proportion of pts achieving BM-uMRD and CR, including pts with TP53-aberrant disease. The AE profile is favorable, with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Updated data will be presented at the meeting for this ongoing study. Based on our initial results we have opened an expansion cohort to further characterize the efficacy and safety of AVO. AVO will also be studied head-to-head against chemoimmunotherapy and the AV doublet in the phase 3 trial CL-311 (NCT03836261), which is currently enrolling. Figure Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Jacobson:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses. Jacobsen:Astra-Zeneca: Consultancy; Novartis: Research Funding; F. Hoffmann-LaRoche: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Armand:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Brown:BeiGene: Consultancy; AbbVie: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Juno/Celgene: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. OffLabel Disclosure: Acalabrutinib, venetoclax, obinutuzumab - combination therapy for previously untreated CLL

Description: Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

Description: Key Points IGH translocations in myeloma can occur through at least 5 mechanisms. t(11;14) and t(14;20) DH-JH rearrangement-mediated translocations occur indicating these appear to occur in a pregerminal center cell.

Description: Key Points Donor T-Rapa cells were composed of Th1 and Th2 effectors with a reproducible gene expression profile. Preemptive T-Rapa donor lymphocyte infusion was safe and associated with donor engraftment without excessive GVHD.

Description: Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by severe chronic neutropenia from birth, premature death secondary to infectious complications, and transformation to myeloid malignancy. Although many cases of SCN are associated with mutations in ELANE, encoding the neutrophil elastase, roughly one-third of cases do not have an identifiable genetic cause. In collaboration with the Severe Chronic Neutropenia International Registry (SCNIR), we performed exome sequencing on 90 cases of congenital neutropenia. Heterozygous missense mutations of CLPB were identified in six patients with SCN. None of these patients had mutations in other genes known to cause SCN. A total of 5 different mutations were identified that clustered within the ATPase domain. Of note, all of these mutations were predicted to be functionally deleterious and had a frequency of

Description: Essential thrombocythemia (ET) is heterogeneous with respect to natural history, X-chromosome inactivation patterns (XCIPs), and presence of the V617F mutation in Janus kinase 2 (JAK2). We studied 111 patients with ET; 39% were JAK2 mutant positive, and clone size (percentage mutant JAK2) was concordant with XCIP when constitutive T-cell patterns were taken into account. JAK2 mutant clones were present in both clonal and polyclonal cases as determined by XCIP, and the former had higher mutant JAK2 levels (median 26% versus 16%; P = .001). No change was observed in serial XCIP analysis of 14 polyclonal patients over a median follow-up of 61 months. Furthermore, 18 of 19 mutant-positive patients showed no significant change in mutant JAK2 level over a median follow-up of 47 months. These results suggest that, in many cases of ET, a small stable clone containing a JAK2 mutation can be maintained as a subpopulation for many years.

Description: Key Points In ET, a CALR mutation correlates with a monoclonal X chromosome inactivation pattern, which differs from JAK2V617F mutant disease. The presence of a CALR mutant is associated with suppression of wild-type myelopoiesis.