Strategies to reduce relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia.

The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant

Anti-CD45 Pretargeted Radioimmunotherapy Prior to Bone Marrow Transplantation without Total Body Irradiation Facilitates Engraftment From Haploidentical Donors and Prolongs Survival in a Disseminated Murine Leukemia Model

s / Biol Blood Marrow Transplant 19 (2013) S211eS232 S228 chemotherapy was HIDAC (1-3 grams/m2 for 6-8 doses)/ Etoposide(15-40mg/kg) in 16 patients and growth factor alone in one patient. Median time from diagnosis to ASCT was 4.2 (range 3.6-7) months. Preparative regimen for ASCT was Busulfan (3.2mg/kg x 4)/Etoposide (60 mg/kg) in 12 patients and high dose melphalan in 5 patients. The median CD34 cells infused was 4.9 x 10e6/kg (range 2.8 to 15.9).All patients engrafted with a median time to neutrophil engraftment of 11 (range10-12) days. The median time to platelet engraftment was 20 (range15-40) days. The median length of inpatient stay during the ASCT admission was 14 (range 10-25) days. One patient died of progressive disease 14 months post ASCT. Two patients died in remission on day 53 (sepsis) and day 836 (unknown cause) post ASCT. Fourteen patients (82%) are currently alive in complete remission. at a median follow-up of 20 (range 140) months post ASCT. Conclusion: Consolidation of good risk AML patients with ASCT following induction of complete remission is safe and effective in preventing relapse in good risk AML patients

The role of adjuvant chemotherapy in the management of acute promyelocytic leukemia differentiation syndrome.

Acute Promyelocytic Leukemia (APL) is characterized by the t(15;17) chromosomal translocation resulting in a PML-RARA fusion protein. The all-trans-retinoic acid (ATRA) and Arsenic Trioxide (ATO) only regimens have demonstrated success in treating low- and intermediate-risk patients. However, induction with ATRA/ATO only regimens have been showing increased incidence of differentiation syndrome (DS), a potentially lethal complication, traditionally treated with dexamethasone. We conducted a three-institution retrospective study, aiming to evaluate the role of short-term adjuvant chemotherapy in managing moderate DS for patients with low- or intermediate-risk APL initially treated with ATRA/ATO only protocols. We evaluated the difference in incidence and duration of moderate DS in APL patients who were treated with ATRA/ATO with or without adjuvant chemotherapy. 57 low- or intermediate-risk APL patients were retrospectively identified and included for this study; 36 patients received ATRA/ATO only induction treatment, and 21 patients received ATRA/ATO/adjuvant chemotherapy combination induction therapy. Similar proportions of patients experienced DS in both groups (66.7% vs. 81.0%, P = 0.246). The median duration of DS resolution in patients receiving ATRA/ATO only was 17 days (n = 23), and in patients receiving combination therapy was 8 days (n = 16) (P = 0.0001). The lengths of hospital stay in patients receiving ATRO/ATO only was 38 days (n = 7), and in patients receiving combination therapy was 14 days (n = 17) (P = 0.0007). In conclusion, adding adjuvant chemotherapy to ATRA/ATO only protocol may reduce the duration of DS and the length of hospital stay during APL induction treatment

A Single Center Retrospective Study of Real World Relapsed/Refractory DLBCL Patients Eligible for CAR T-Cell Therapy: Patient Characteristics and Outcomes

Introduction: Patients with Diffuse large B-cell lymphoma (DLBCL) may experience excellent long-term outcomes after initial anthracycline containing therapy. However, patients with relapsed or refractory (R/R) DLBCL often have poor outcomes. Select R/R DLBCL patients may be treated with additional chemoimmunotherapy (CIT) followed by hematopoietic stem cell transplant (HSCT). However, as many as 50% of R/R DLBCL patients are unable to undergo HSCT due to lack of response to CIT or comorbidities (Gisselbrecht C, et al JCO 2010). Recent data reported in the SCHOLAR-1 study suggest a median overall survival (OS) of 6.3 months for these patients, with only 20% of patients alive at 2 years (Crump M, et al Blood 2017). Chimeric antigen receptor T-cell (CAR-T) therapy, a novel form of immunotherapy, offers improved outcomes for such patients with complete response rates of approximately 40% and 50% OS at 12 months or greater (Neelapu SS et al. NEJM 2017; Borchmann P et al, EHA 2018). Delivery of CAR-T therapy is specialized and remains limited to a small number of centers at present. The broad applicability of CAR-T therapy in a real world population of R/R DLBCL patients remains unknown. This retrospective study aimed to identify the characteristics and outcomes of a cohort of R/R DLBCL patients who would have been eligible for CAR-T cell therapy if available over a 4 year period at Swedish Cancer Institute (SCI). The SCI is a specialty cancer research center, based in a non-profit, non-university affiliated medical center. Methods: All patients with recorded diagnosis of DLBCL (ICD9/10) seen for an outpatient encounter in a SCI facility between the dates of 01/01/2014 and 01/01/2018 were identified from an electronic medical record database. Patients who had received anthracycline-based chemotherapy only at SCI as initial therapy and then subsequently received 2nd line or beyond therapy at SCI between January 2014 and January 2018 were included. This population was defined as the study cohort of R/R DLBCL patients and was then evaluated for would-be eligibility for CAR-T therapy by application of the defined Kite Zuma-1 clinical trial Inclusion/Exclusion (I/E) criteria. Patient characteristics for the CAR-T eligible population were obtained by retrospective medical record review. Overall survival of the potential CAR-T eligible population was assessed including stratification by receipt of HSCT at any time during the study period. Results: 486 patients with a diagnosis of DLBCL were seen during outpatient SCI encounters between Jan 2014 and Jan 2018. Of these, 60 patients received prior 1st line anthracycline therapy exclusively at SCI and then received 2nd line or beyond therapy at SCI between 2014 and 2018 for R/R DLBCL. The majority of patients, 82% (n=49), met all Zuma-1 I/E criteria for CAR-T therapy. Characteristics of these patients are identified in Table 1. Among all CAR-T eligible patients, OS was 37.1% at 24 months (Figure 1). Patients received a variety of 2nd line or beyond therapies, including 47% (n=23) who received HSCT. OS at 24 months for CAR-T eligible patients was significantly better for those receiving HSCT in 2nd line or beyond versus those who did not receive HSCT (61.6% vs 12.0%, respectively; p\u3c0.001; Figure 2). Conclusion: In a retrospective cohort of real-world R/R DLBCL patients treated between 2014 and 2018 at SCI, a non-university based specialty cancer research center, 49 of 60 patients (82%) would have been eligible for CAR-T therapy based on Zuma 1 I/E criteria. This suggests that the majority of the patients with R/R DLBCL in the real-world may have an opportunity to receive CAR-T. Moreover, while those who underwent a successful HSCT as part of 2nd line or beyond therapy had greatly improved outcomes, those patients who did not undergo HSCT had poor outcomes. For such patients not receiving HSCT, the availability of CAR -T may lead to significantly improved outcomes

The Efficacy of Passive Valve Antimicrobial Swab Caps Against Existing Clabsi Prevention Bundle in an Adult Hematology Inpatient Population: A Quality Improvement Initiative

Background: Central line associated blood stream infections (CLABSI) have been the costliest of all healthcare associated infections. The average CLABSI cost is approximately 46,000 (Haddadin & Regunath, 2019). Most cases may be preventable with utilization of aseptic techniques, surveillance, and management through local protocols. The majority of CLABSI occur more than five days after central vascular access (CVA); therefore, there has been a growing focus on central line handling and maintenance techniques. CLABSI prevention data has been largely focused on the intensive care unit (ICU) patient population where an average of about half of patients have CVA. There have been few studies exploring the rates of CLABSI in the adult hematology population, a population with unique risk factors due to their immunosuppressing treatments and prolonged immunocompromised states. There has been emerging data that suggests the use of new technology in addition to existing central line maintenance recommendations by the Center for Disease Control may further reduce the rate of CLABSI occurrences in high-risk patient populations. Aim: To determine the efficacy of passive valve antimicrobial swab caps on the reduction of CLABSI in an inpatient hematology patient population when compared to current existing local practices. Outcomes of reported incidents of CLABSI have been evaluated against pre-interventional data for this setting. Methods: Retrospective analysis of medical records from January 2016 - September 2019 identified the existing rate of CLABSI occurrence among inpatient hematology patients at a single institution. We utilized the intervention of antimicrobial swab caps for 10 months and tracked the rate of CLABSI during this time. The nursing staff were educated on the quality improvement project, the use of the new equipment, and expectations that existing standard practices per local policy for CLABSI prevention bundles would be adhered to prior to the start of the intervention. To evaluate the impact of the antimicrobial swab caps on the rate of CLABSI we compared the number of infections pre- and post-intervention. Randomized audits, including chart reviews for compliance with existing standard CLABSI bundle practices were performed during the initial 3 months of the intervention. Results: Prior to the introduction of the passive valve antimicrobial swab cap to the existing CLABSI prevention protocol, CLABSI rates on the hematology unit exceeded the standardized infection ratio 75th percentile on 9 of the previous 15 calendar quarters. The intervention was observed for 6,674 central line days. The CLABSI rate during the intervention was 0.4495 per 1,000 central line days. The CLABSIs identified were due to nosocomial opportunistic infection in setting of immunosuppressed status (66%) and gastrointestinal translocation (33%). The common diagnosis in setting of CLABSI was refractory/relapse diffuse large B-cell lymphoma (66%) and active acute myeloid leukemia (33%). The two patients who were diagnosed with CLABSI were neutropenic with an absolute neutrophil count of 0 at time of CLABSI diagnosis. The organisms identified at time of CLABSI diagnosis were Clostridium ramosom, Enterococcus faecium, Staphylococcus epidermisis, and Candida parapsilosis. When considering the cost of a CLABSI to be about 46,000 per event and the annual cost for the inpatient hematology unit\u27s use of the caps of approximately $19,710, the implementation of the antimicrobial swab cap reduced the cost associated with CLASBI in the hematology unit by approximately$26,290 annually. Conclusions: The introduction of the passive valve antimicrobial swab caps appears to demonstrate potential for reduced costs due to CLABSI when implemented into current CLABSI prevention bundles. This resulted in a 25% reduction in rates of CLABSI in the adult hematology patient population when compared to the previous year. The prevention of CLABSI in hematology patients with central vascular access remains challenging, however, standardized protocols for CLABSI prevention and use of antimicrobial swab caps may help further reduce the rate of CLABSI in hematology patients

Initial Safety Results from a Phase II Study of Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis despite therapies using second-line chemoimmunotherapy (CIT). Achievement of complete response (CR) with second-line therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve CR with standard CIT regimens alone. The addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to second-line therapy may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. BTK has been shown to be essential for BCR-mediated activation of the NF- κB/Rel family of transcription factors and BCR signaling has been recognized as a key pathway in the pathogenesis of DLBCL. Moreover, NF-κB activity relies upon chronic active BCR signaling in activated B-cell-like DLBCL, which can be potentially blocked by kinase inhibitors targeting BTK. In this study we examine the feasibility and efficacy of adding the BTKi, acalabrutinib (A), to standard second-line therapy to improve disease response in patients with R/R DLBCL. Here we present initial safety and tolerability data for the ongoing study. Study Design and Methods: This is an open-label, prospective phase II trial (NCT03736616). Cohort A is open to R/R DLBCL patients eligible for autologous hematopoietic transplantation (HCT). Cohort B is open to R/R DLBCL patients considered ineligible for autologous HCT. The primary endpoint for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) prior to autologous HCT in patients undergoing second-line CIT. The primary endpoint for cohort B is defined as the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy. Cohort A receive 2 cycles of standard RICE salvage CIT in combination with acalabrutinib, 100mg BID days 1-21 of a 21-day cycle (RICE+A). After 2 cycles of therapy, patients undergo autologous stem cell mobilization and collection. Patients then receive a 3 rd cycle of RICE in combination with acalabrutinib. PET-CT (PET3) is to be performed on day 15 of cycle 3 to assess response. Patients with CR or partial response (PR) after PET3 proceed to autologous HCT with BEAM conditioning within 28-42 days of PET3. Post-HCT CR patients receive acalabrutinib 100mg BID as maintenance therapy for 12 additional months. Protocol amendment in May 2021 allows for PET assessment (C2D15) prior to autologous stem cell collection (after cycle 3). Cohort B receive 3 cycles of RICE+A in 21-day cycles followed by PET-CT (PET3) on day 15 of cycle 3. Patients without progressive disease at PET3 continue with acalabrutinib maintenance up to 12 additional cycles until disease progression or unacceptable toxicity. Patients demonstrating progressive disease are withdrawn from study treatment but followed for outcomes. Results: Here we report initial safety and tolerability data for the ongoing study with data cutoff July 28, 2021. Twenty-two patients have been screened and 20 patients have received at least 1 cycle of RICE+A. Patient characteristics are shown in Table 1. Fifteen patients (79%) have completed 3 cycles of RICE+A. One patient (5%) discontinued due to an adverse event (AE; recurrent appendicitis), 3 patients (16%) discontinued due to progressive disease, and 1 patient is receiving ongoing RICE+A as of data cutoff. Hematologic AE have been observed in 17 patients (89%) with 74% being Grade 3/4. Amongst these, neutropenia was the most common AE occurring in 47% with all being Grade 3/4, and thrombocytopenia occurring in 32% with all being Grade 3/4. All hematologic AE recovered to baseline or grade 1 in median 7 days. Amongst non-hematologic AE, diarrhea occurred in 21% and 0% were Grade 3/4, nausea 16% with 0% Grade 3/4, and headache in 16% with 0% Grade 3/4. Discontinuation of therapy due to AE occurred in 1 patient (recurrent appendicitis) and dose reduction occurred in 1 patient (Gr 4 neutropenia). Temporary (per protocol) dose holds of A occurred in 9 patients (45%), primarily for cytopenias during concurrent RICE+A. Median duration for dose holds of A was 5.5 days. Conclusion: RICE+A is feasible with manageable primarily hematologic AEs similar to those reported for RICE alone. Enrollment and follow up is ongoing for efficacy endpoints and further toxicity assessment

Phase 1/2 Study Investigating CC-90011, a Potent, Selective, and Reversible Oral Inhibitor of Lysine-Specific Demethylase 1 (LSD1), Plus Concurrent Venetoclax (VEN) and Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML)

Abstract Background AML may be initiated by cytogenetic alterations or mutations in genes encoding epigenetic regulators. Epigenetic dysregulation influences the transformation of hematopoietic stem cells or their downstream progenitors into self-renewing leukemic stem cells (LSCs), which contribute to AML pathogenesis and tumor growth. Residual chemoresistant LSCs are implicated in relapsed and/or refractory (R/R) AML, a life-threatening disease with limited treatment options. The epigenetic eraser LSD1 demethylates histone lysine residues to alter gene expression, is essential for hematopoiesis, and is often overexpressed in LSCs in AML. CC-90011 is a potent, selective, and reversible oral inhibitor of LSD1 that has shown antitumor effects in solid-tumor and AML cell-line models. CC-90011 monotherapy had a favorable safety profile and showed evidence of antitumor activity in patients with advanced solid tumors and R/R non-Hodgkin lymphoma (Hollebecque et al. ESMO TAT 2021. Abstract 7O). CC-90011 combined with etoposide plus carboplatin or cisplatin was well tolerated in patients with extensive-stage small cell lung cancer (Ponce at al. ELCC 2021. Abstract 50P). VEN plus AZA has emerged as standard therapy for elderly patients with AML. Adding CC-90011 to VEN and AZA may inhibit the aberrant LSD1 activity associated with AML pathogenesis and LSC propagation, increase sensitization to VEN and AZA, and produce deeper and more durable responses than VEN plus AZA alone. Study Design and Methods CC-90011-AML-002 (NCT04748848) is a phase 1/2, open-label, multicenter study to evaluate the safety, tolerability, and preliminary efficacy of CC-90011 plus concurrent VEN and AZA in adult patients with R/R AML or in patients with newly diagnosed AML (ndAML) who are ≥ 75 years of age or are 18-74 years of age and ineligible for intensive induction chemotherapy. The study has 2 dose-escalation parts in patients with R/R AML (part 1) or ndAML (part 2), and a randomized dose-expansion part in patients with ndAML (part 3). Part 3 will use a 2:1 randomized design with Bayesian informative prior to calculate the posterior probability that the complete remission (CR) rate in the treatment arm is higher than in the control arm. Enrolled patients must have a projected life expectancy of ≥ 12 weeks, ECOG performance status of 0-2, white blood cell count ≤ 25 × 10 9/L, and adequate organ function. Patients will be excluded if they are candidates for FLT3 inhibitor therapy or have suspected or proven acute promyelocytic leukemia, favorable-risk cytogenetics, or central nervous system involvement. In parts 1 and 2, patients will receive CC-90011 20, 40, or 60 mg plus VEN and AZA (3-6 patients per treatment arm). In part 3, patients will receive VEN plus AZA with or without CC-90011 administered at the recommended phase 2 dose (RP2D) determined in part 2 (approximately 64 and 32 patients, respectively), with an interim analysis for futility once 50% of patients have been randomized and completed 3 treatment cycles. In all parts, CC-90011 will be administered orally on days 1, 8, and 15 of each 28-day cycle, AZA 75 mg/m 2 will be administered intravenously or subcutaneously on days 1-7 of each cycle, and oral VEN 400 mg will be administered on days 1-28 of each cycle, with a dose ramp-up on days 1 and 2 of cycle 1. VEN will be given ≥ 6 hours after CC-90011 to minimize drug-drug interactions. For clinical outcome evaluation, patients should be treated for ≥ 3 cycles but can discontinue sooner due to disease progression, unacceptable adverse events, intercurrent illness, or investigator's decision. Primary objectives are to evaluate the safety and tolerability of CC-90011 plus VEN and AZA, and to determine the maximum tolerated dose and/or RP2D of CC-90011. Secondary objectives are to assess the preliminary efficacy of CC-90011 plus VEN and AZA in parts 1-3, and to evaluate the minimal residual disease (MRD) response and conversion rates by multicolor flow cytometry and/or next-generation sequencing in parts 2 and 3. Preliminary efficacy will be determined using CR rate, rate of CR with partial or incomplete hematologic recovery, overall response rate, and duration of response in parts 1-3, and event-free and overall survival in part 3. Because CC-90011 is expected to target LSCs, its addition to VEN plus AZA is predicted to increase the depth and durability of response by MRD evaluation compared with control, rather than increase remission rates. Figure 1 Figure 1. Disclosures DiNardo: AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; GSK: Consultancy; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee. Mawad: Abbvie: Speakers Bureau. Kremyanskaya: Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; Astellas: Research Funding; Bristol Myers Squibb: Research Funding; Chimerix: Research Funding; Astex: Research Funding. Blachly: AstraZeneca: Consultancy, Honoraria; KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; AbbVie: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Youn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Garzon: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Martin-Regueira: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Watts: Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding