Previous Autologous Stem Cell Transplantation Research Articles

Acalabrutinib in Combination with Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory B-Cell Lymphoma: A Phase I/II Study of Safety, Efficacy and Immune Correlative Analysis

Introduction Limitations of effective CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T) in relapsed/refractory (R/R) B-cell lymphoma include inability to control disease prior to CAR-T, lack of sustained remissions following CAR-T and the potential for life-threatening adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). BTK inhibitors, ibrutinib and acalabrutinib are immunomodulatory and may enhance CAR-T expansion, engraftment and tumor clearance while decreasing the frequency and severity of CRS in chronic lymphocytic leukemia (Qin, et al. J Immunother 2020). Based on this, we hypothesized that acalabrutinib, when combined with CD19-targeted CAR-T, could enhance its efficacy and safety and may also serve as an effective bridging strategy. We report the initial safety, efficacy and correlative analysis of acalabrutinib in combination with axicabtagene ciloleucel (axi-cel) in R/R B-cell lymphoma. Methods We conducted a phase I/II, open-label trial (NCT04257578) involving adult patients meeting FDA-approved criteria for axi-cel; this included patients with R/R CD19+ large B-cell (LBCL) and follicular lymphoma (FL) with measurable disease. Acalabrutinib was continuously administered at 100 mg twice daily over the 3 study phases: 1) Bridging: Starting between 3 weeks and 24 hours prior to leukapheresis until lymphodepletion (LD), 2) Cell therapy: From LD to 30 days after axi-cel infusion, 3) Maintenance: From 30 days to 1 year after axi-cel infusion or until unacceptable toxicity or disease progression (Figure 1). Axi-cel was administered per institutional practice. The primary endpoint was safety based on rates of grade ≥3 CRS or ICANS within 30 days of axi-cel infusion. We also assessed bridging success rate (defined as receipt of axi-cel without any additional required treatment), overall response rate (ORR) and complete response (CR) rate following axi-cel infusion, progression-free survival, overall survival and immune response biomarkers. Results As of July 28, 2023, 17 patients have enrolled, 14 have received axi-cel infusion and are evaluable for response to CAR-T and 3 are earlier in treatment. Fourteen patients had LBCL (12 DLBCL [4 with double/triple hit, 3 with double/triple expressor, 1 with only MYC translocation] and 2 PMBCL) and 3 had FL (Table 1). Median age was 58 (range 34-74) years, largest lesion diameter was a median of 3.75 (1.7-7.1) cm and the median number of prior regimens was 3 (range 1-5). Of LBCL patients, 6 (43%) had primary refractory disease and 5 (38%) had relapsed within 12 months of initial therapy; 4 (31%) patients had previous autologous stem cell transplant. Fourteen of 15 patients (93%) who underwent axi-cel infusion were successfully bridged from prior to leukapheresis to LD with single agent acalabrutinib and no additional therapy; 1 received added radiation. After cell infusion, 13 (93%) and 8 (57%) patients had any grade CRS and ICANS, respectively. Three (20%) patients had grade 3 ICANS which resolved with dexamethasone and anakinra or tocilizumab. No patients received prophylactic dexamethasone. No patients experienced grade ≥3 CRS or any grade hemorrhage or tachyarrhythmia. No patients discontinued acalabrutinib at any time due to toxicity, meeting an interim safety endpoint. The ORR and CR rate at day 30 post axi-cel infusion was 93% and 71%, respectively. Through post axi-cel maintenance, there were no drug holds. One of the 3 patients with partial remission (PR) at day 30 converted to CR at day 180 post infusion while 2 suffered disease progression at day 90 post axi-cel infusion. No treatment related deaths were observed by time of data cutoff. At a median follow-up of 13.8 (range 1.7-29.1) months, 10 (73%) patients are alive and 9 are progression-free. Post axi-cel cytokines peaked at a median of day 6 [median IL-6 196 pg/ml (range 20-11803), ferritin 425 ng/ml (156-2051), CRP 52.9 mg/L (7.7-239.7), Table 1]. Impact of acalabrutinib on myeloid derived suppressor cells and the immunosecretome profile are underway and will be reported at time of presentation. Conclusions Acalabrutinib successfully bridged most patients in this trial when given concurrently with axi-cel and safely maintained high CR rates. CRP and ferritin levels were typically only modestly elevated after cell infusion. Severe CRS was not observed and high-grade ICANS was uncommon.

Intent to Treat Allogeneic Stem Cell Transplantation Outcomes in Relapsed/Refractory T-Cell Lymphomas

Introduction T-cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative malignancies with an overall poor prognosis. Despite aggressive first-line therapy, most patients experience disease relapse or progression. Allogeneic stem cell transplant (AlloSCT) is a standard of care for relapsed/refractory (R/R) TCL. However, many patients do not receive this potentially curative therapy. There is a paucity of data regarding the frequency of and barriers to undergoing AlloSCT in R/R TCL. To address this knowledge gap, we conducted a retrospective analysis of R/R TCL patients intending to undergo AlloSCT and hypothesized the primary barrier to AlloSCT to be lack of effective disease control. Methods We identified patients with a primary diagnosis of R/R TCL seen at the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC) between 1/2008 and 6/2023 and linked these patients with the UW/FHCC bone marrow transplant (BMT) database to identify those who were intended for transplant. Intention to transplant (ITT) was defined as undergoing human leukocyte antigen (HLA) typing for purposes of AlloSCT. Patients with T-cell lymphoblastic leukemia/lymphoma were excluded. The primary endpoint was the rate of patients who underwent AlloSCT. Secondary endpoints included progression-free (PFS) and overall survival (OS) in patients who underwent AlloSCT and specific barriers to AlloSCT. Results Overall, 163 patients met ITT criteria. Males comprised 66% of patients. Median age was 65 (range 34-81) years and the median number of treatment regimens prior to HLA typing was 3 (range 1-10). The majority of patients (60%) were non-Hispanic whites (NHW), with Asians/Pacific Islanders (API), Hispanics/Latinos (HL), African Americans (AA) and Alaskan Natives/American Indians (ANAI) contributing 17%, 12%, 7% and 4%, respectively. Sixty-four patients (39%) had peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 23 (14%) had angioimmunoblastic TCL (AITL), 17 (10%) had anaplastic large cell lymphoma (ALCL; 6 with ALK+), 16 (10%) had NK/TCL, 11 (7%) had hepatosplenic TCL, 12 (7%) had T-cell prolymphocytic leukemia, 5 (3%) had adult T-cell leukemia/lymphoma and 12 (7%) had primary cutaneous TCL. Twenty-two (13%) patients had secondary CNS involvement and 27 (17%) had previous autologous stem cell transplant. Of all patients who received HLA typing, 154 (94%) had a transplant consult, 54 (33%) initiated pre-AlloSCT workup and 51 (31%) underwent AlloSCT. Barriers to AlloSCT included progressive disease, patient preference, inability to identify a donor, indolent disease, poor functional status/multiple comorbidities and lack of a caregiver in 55%, 9%, 8%, 5%, 3% and 1%, respectively (Figure 1A). Six (5%) patients are currently receiving salvage therapy with plans for subsequent AlloSCT. AlloSCT occurred in NHW, API, HL, AA and ANAI patients at rates of 35%, 11%, 26%, 36% and 50%, respectively. All patients who were unable to undergo transplant due to lack of a donor were from groups other than NHW. AlloSCT rates were 30%, 39% and 17% in PTCL-NOS, AITL and ALCL, respectively. At a median follow-up time of 24.2 months, 101 (63%) patients are deceased with 83 (82%) due to disease. Twenty (39%), 17 (33%), 11 (22%) and 3 (6%) patients received an AlloSCT with a matched unrelated, matched related, mismatched unrelated and haploidentical donor, respectively. Fifteen (29%) patients underwent a myeloablative while 36 (71%) underwent a reduced intensity conditioning regimen. None of the 51 patients who underwent AlloSCT had pre-transplant measurable disease. Of transplanted patients, median PFS was 55.7 months and OS was 62.4 months (Figure 1B). Sixteen (31%) patients had eventual disease relapse. Eighty percent of relapses occurred within 3 months after AlloSCT. Seven (13%) and 6 (12%) of the transplanted patients were deceased within 12 months after AlloSCT due to disease relapse and complications of AlloSCT, respectively. Conclusions Although AlloSCT may be highly effective for R/R TCL achieving a CR, only a small minority of patients are able to undergo AlloSCT and the outcomes for the ITT population is dismal. Common barriers to undergoing AlloSCT include progressive disease and inability to identify suitable donors, particularly in minority populations. More effective pre-transplant salvage therapies and alternative AlloSCT donors are greatly needed.

A First-in-Human Phase I Study of AT101, a Novel Anti-CD19 Chimeric Antigen Receptor T Cell Product Targeting a Membrane-Proximal Domain of CD19 in Adults with Relapsed or Refractory B Cell Non-Hodgkin Lymphoma

Introduction: Anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are highly efficacious against advanced B cell non-Hodgkin lymphoma (NHL) but the majority of patients (pts) ultimately fail. Several mechanisms contribute to CART19 failure, including CD19-neg escape and CART dysfunction. Notably, all four commercial CART19 products utilize the FMC63 single chain variable fragment (scFv) with high-avidity specificity to a CD19 membrane-distal epitope. Interestingly, loss of the FMC63-recognized epitope due to CD19 mutations ( Zhang Z, JITC, 2020) or epitope-masking (CAR19:CD19) ( Ruella M, Nat Med, 2018) has been described. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 with low avidity could: 1. mitigate CD19 epitope loss; but also 2. enhance CART functions ( Fig. 1A) . Methods and results: We developed an autologous, CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218) specific to a membrane-proximal epitope of CD19 (amino acids T51,S53, E55,K59 and K63). We previously reported initial preclinical data ( Patel R., ASH, 2021 #2798) that demonstrated h1218-CART19 recognize and kill B-cell leukemia that aberrantly expresses the FMC63-CAR19. More recently, we demonstrated that differently than FMC63-based CART, h1218-CART19 could respond to and kill tumor cells expressing point mutations of CD19 (L174V and R163L). Of note, h1218-CART19 had enhanced control of CD19+ B-cell neoplasms as compared to FMC63-CART19 both in vitro and in vivo. Mechanistically, thanks to the lower avidity and faster on/off rate, h1218-CART19 had decreased T cell exhaustion and activation-induced cell death. Given the promising preclinical results, we tested the clinical h1218-CART19 product (AT101) in a first-in-human, multi-center, phase I/II, dose-escalation clinical trial for pts with histologically confirmed relapsed or refractory B cell NHL (NCT05338931). For the phase I study, pts were treated with a single intravenous infusion of AT101 (day 0) in three dose levels (DL) based on a standard 3+3 design: DL1 (0.2 x 10 6 cells/kg), DL2 (1.0 x 10 6 cells/kg), or DL3 (5.0 x 10 6 cells/kg). All pts received lymphodepletion with intravenous fludarabine (250 mg/m 2) and cyclophosphamide (25 mg/m 2) on days -4, -3, and -2. The primary objective was to determine the maximum tolerated dose (MTD) of AT101. The secondary objectives were to evaluate AT101 pharmacokinetics and preliminary efficacy. At the July 3, 2023 data cut, 12 pts (median age 62.5 years (range 39-84); diffuse large B cell lymphoma (DLBCL, n=7, 58.3%), follicular lymphoma (FL, n=3, 25.0%), mantle cell lymphoma (MCL, n=1, 8.3%), and marginal zone lymphoma (MZL, n=1, 8.3%)) received AT101 ( Fig. 1B). The median follow-up after AT101 was 6.5 months (1.5-13.7 months), the median number of previous lines of treatment 3 (range 1-8); no prior cellular therapies. Five pts (41.7%) had previous autologous stem cell transplantation. Two pts (16.7%) had refractory disease and two pts (16.7%) received bridging therapy. Three pts (2 pts at DL2 and 1 pt at DL3) developed a grade (G) 1 cytokine-release syndrome (CRS) and one pt at DL3 developed a G3 CRS that resolved within 24 hours. Three pts (1 pt at each DL) developed immune-cell-related neurotoxicity syndrome (ICANS), of which one G4 dose-limiting toxicity (DLT) was reported at DL1 that corrected within 6 days. One DL3 pt experienced G3 sepsis that promptly resolved; the same pt ultimately developed fatal neutropenic septic shock outside the DLT period. Four additional patients experienced ≥G3 neutropenia without evidence of infection. Complete response (CR) occurred in 8/12 pts (66.6%) and overall response (CR+partial response) in 83.3% (95%CI, 51.6-97.9) at day 28 post-AT101 infusion ( Fig. 1B). Remarkably, in DL2 and DL3, the CR rate was 100.0%. Of the 8 pts in CR none has relapsed (median follow-up 6.0 months). AT101 cells expanded (peak in DL3 113.6 ± 6.50 x10 4 CAR gene copies/ug DNA) and persisted in patients' blood. Conclusion: In this first-in-human phase I trial, AT101 was tolerable with limited and manageable toxicities. Notable preliminary efficacy was observed at the RP2D with no evidence of disease relapse after achieving a CR. These results warrant the pursuit of the planned phase II expansion cohort.

The salvage role of allogeneic hematopoietic stem-cell transplantation in relapsed/refractory diffuse large B cell lymphoma

To clarify the role of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the chimeric antigen receptor T-cell therapy era, we analyzed the clinical characteristics and outcomes of 52 patients treated with allo-HSCT with relapsed/refractory diffuse large B cell lymphoma. Most enrolled patients had previously undergone intensive treatments, the median number of chemotherapy lines was 4, and the median time from diagnosis to allo-HSCT was 27.1 months. Patients were divided into remission-achieved (n = 30) and active-disease (n = 22) groups before allo-HSCT. Over a median follow-up period of 38.3 months, overall survival (OS) and event-free survival (EFS) rates were 38.4% and 30.6%, respectively. The cumulative incidence of relapse (CIR) and the non-relapsed mortality (NRM) were 36.7% and 32.7%, respectively. OS, EFS, and graft-versus-host disease-free, relapse-free survival (GRFS) outcomes were significantly superior in the remission-achieved group with lower CIR. In a multivariate analysis, a shorter interval from diagnosis to allo-HSCT reflected relatively rapid disease progression and showed significantly poor OS and EFS with higher CIR. Patients with active disease had significantly lower EFS, GRFS, and higher CIR. Previous autologous stem-cell transplantation was associated with better GRFS. Allo-HSCT is an established modality with a prominent group of cured patients and still has a role in the CAR T-cell era, particularly given its acceptable clinical outcomes in young patients with chemo-susceptible disease.

Clinical Outcomes of Patients with Multiple Myeloma after Daratumumab Failure.

Anti-CD38 monoclonal antibody (MoAB) therapy has significantly improved the prognosis of patients with multiple myeloma. However, not all patients sustain durable responses. We aimed to describe the natural history of patients relapsed or refractory (R/R) to CD38 MoAB therapy. We performed a single-center, retrospective analysis of the clinical characteristics and outcomes of 81 patients with multiple myeloma who progressed after treatment with daratumumab. Our cohort was heavily pretreated, with a median of two lines prior to daratumumab and only 17 patients received daratumumab as a first line. A total of 38.2% had received a previous autologous stem cell transplantation (ASCT), and 61.7% had received both an immunomodulatory drug (IMID) and a proteasome inhibitor (PI). The median overall survival (OS) was 21 months for the global cohort but it decreased to 14 months for triple-class refractory patients and 5 months for penta-refractory patients. Most of the patients (83.9%) received treatment after daratumumab progression, in many cases with second generation IMID or PI, but seven patients were treated with anti-BCMA therapy and three patients received CART therapy within a clinical trial. In conclusion, patients R/R to daratumumab represent an unmet clinical need with poor prognosis and in need of incorporation of new treatments.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial

γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies

IntroductionMelphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN. MethodsThese analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022). ResultsIn OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports. ConclusionThese analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).

Carfilzomib, lenalidomide, and dexamethasone in relapsed refractory multiple myeloma: a prospective real-life experience of the Regional Tuscan Myeloma Network.

Carfilzomib, a potent, irreversible, selective proteasome inhibitor has demonstrated consistent results in relapsed/refractory multiple myeloma (RRMM) combined with lenalidomide and dexamethasone (KRd). No prospective studies are yet available that analyzed the efficacy of the KRd combination. Herein, we report a multicenter prospective observational study on 85 patients who were treated with KRd combination as the second or third line of treatment, according to standard practice. The median age was 61 years; high-risk cytogenetic was found in 26% and renal impairment (estimated glomerular filtration rate (eGFR) <60 ml/min) in 17%. After a median follow-up of 40 months, patients received a median number of 16 cycles of KRd, with a median duration of treatment (DoT) of 18 months (range, 16.1-19.2 months). The overall response rate was 95%, with a high-quality response (≥very good partial remission [VGPR]) in 57% of the patients. The median progression-free survival (PFS) was 36 months (range, 29.1-43.2 months). Achievement of at least VGPR and a previous autologous stem cell transplantation (ASCT) were associated with longer PFS. The median overall survival (OS) was not reached (NR); the 5-year OS rate was 73%. Nineteen patients underwent KRd treatment as a bridge to autologous transplantation, obtaining a post-transplant minimal residual disease (MRD) negativity in 65% of cases. The most common adverse events were hematological, followed by infection and cardiovascular events, rarely G3 or higher, with a discontinuation rate for toxicities of 6%. Our data confirmed the feasibility and safety of the KRd regimen in real life.

Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma in a Real-Life Population in France: The Remix Study

Background Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Efficacy and safety have been demonstrated in the phase 3 Tourmaline-MM1 clinical trial (1), which has recently reported the longest median overall survival (mOS) in phase III studies of Rd-based triplets (53.6 months, mo) (2). The REMIX study has been conducted since IXA became available in France in 2017. It is the largest cohort of RRMM pts receiving IXA-Rd combination in real life. The final analysis was performed with a median follow-up of 28.7 mo. Methods REMIX is a non-interventional, prospective study conducted in 59 sites (public and private) in pts with RRMM in France. To be eligible pts had to receive IXA-Rd in second line or later and IXA had to be initiated concomitantly to Rd (pts who started lenalidomide (lena) more than 6 weeks before IXA were excluded). After inclusion, pts were assessed every 3 mo during 24 mo and then every 6 mo as per standard practice. Analysis comprised OS, progression-free survival (PFS), overall response rate (ORR), very good partial response (VGPR) and tolerance. The analysis was conducted for the overall population and in subgroups of interest: age and lines of treatment (L2, L3 or L4+). Results A total of 376 eligible pts were included. Median age was 71 years (y) with 18.4% of patients aged ≥80y. At IXA-Rd initiation, 48.8% of pts were frail and 21.8% had renal clearance ≤50 ml/min. Comorbidities were reported in 62.8% of pts, including diabetes (8.8%), renal disease (8.8%) or solid tumour (6.4%). At inclusion, the cytogenetic risk was standard, high or unknown in 44.4%, 12% and 43.6% of pts, respectively. MM was diagnosed at a median of 4y before IXA-Rd initiation. 44.5% of pts had previous autologous stem cell transplantation (ASCT). IXA-Rd was initiated in L2, L3 or advanced lines (L4+) in 60.4%, 18.1% and 21.5% of pts, respectively. Regarding previous treatment received, 66.0% of pts had received IMID (including 39.2% lena and 11.7% pomalidomide), 93.1% had received PI (including 91.7% bortezomib and 7.5% carfilzomib) and 13.9% had received daratumumab. Most pts were previously exposed to lena in L3 (73.5% of L3, n=50/68, for a median duration of 16 mo) and L4+ (91.3% of L4+, n=73/81, for 17 mo) compared to L2 (10.6% of L2, n=24/227, for 18 mo). Out of all pts, 26, (7.9%) were considered lena-refractory during previous therapy. The median washout (WO) period between lena discontinuation and IXA-Rd start was 22.8 mo (SD: ±23.9). IXA was used for a median of 12.4 mo (13 cycles) at a 4-mg dose for 90.4% of pts. The median PFS (mPFS) was 19.1 mo (95% CI: 14.9-21.5) for the overall cohort, with a mPFS of 21.5 mo (95% CI: 19.2-24.8) for L2 (n=213), 21.9 mo (95% CI: 16.2-28.7) for L3 (n=65) and 5.8 mo (95% CI: 4.8-9.4) for L4+ (n=80). In the subgroups of pts aged <80y (n=293) and ≥80y (n=65), mPFS were 19.1 mo (95% CI: 15.9-21.9), and 17.4 mo (95% CI: 10.8-23.0), respectively. The mOS was not reached for the overall cohort; 36mo and 48mo OS rates were respectively 58.3% (95% CI: 52.6%-63.9%) and 52.4% (95% CI: 44.2%-60.5%). The 36mo OS rates were 63.4% (95% CI: 56.1-70.8%), 68.9% (95% CI: 57.1-80.7%) and 35.3% (95% CI: 23.9-46.7%) in L2, L3 and L4+ pts respectively. Among the 331 pts with available response according to investigators, the ORR was 73.1% (79.8% in L2, 70% in L3 and 54.4% in L4+ patients) and the VGPR rate was 45% (52.7% in L2, 41.7% in L3 and 25% in L4+ pts). IXA discontinuation was reported in 74.1% of pts (n=278). Discontinuation was related to AE in 21% of cases (n=79). Serious adverse events (SAE) were reported in 54.3% (n=204), including 57 (15.2%) pts with SAE considered related to IXA. Most frequent (>10%) AEs were diarrhoea (52%), thrombocytopenia (45.9%), asthenia (29.7%), neutropenia (23.6%) and anaemia (22.3%). Conclusion The REMIX study reported a mPFS in real-world conditions of 19.1 mo consistent with MM1 (20.6 mo), while half of patients were considered frail and 39.2% had previously received lenalidomide. The effectiveness in third line of treatment is similar to that in second line but was lower in L4+ as expected (5.7 mo). mOS is not reached at 48mo which aligns with MM1 final analysis. Reported AEs are consistent with the known safety profile of Ixazomib. Funding Takeda Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Stem Cell Transplantation Achieves Long-Term Survival in Extranodal Natural Killer/T-Cell Lymphoma: A Retrospective Analysis of the EBMT Lymphoma Working Party

Introduction Extranodal NK/T-cell lymphomas (ENKTL) represent aggressive lymphoid malignancies predominantly occurring in Asia and South America being rare in the Western world. Stage I/II patients are treated with asparaginase-containing (ASP) chemotherapy and local radiotherapy. For advanced stages III/IV and patients (pts) with relapsed/refractory disease current guidelines recommend ASP-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). These recommendations, however, are mostly based on small series of patients (<20 pts) partly reported decades ago. The largest series reported by CIBMTR comprised 82 pts, most of them still having been treated with anthracycline-containing regimens before HSCT (Kanate AS Br J Haematol 2018,182, 909). Methods We conducted a retrospective analysis of EBMT registry data and data from registries of cooperating Asian centers in China and South Korea. The following inclusion criteria were applied: pts with confirmed ENKTL, age ≥18 years, first HSCT between 2013 and 2020, previous autologous stem cell transplantation allowed. Outcome data were calculated from the day of HSCT until the respective event. Results In total, 137 pts were identified with a median age of 43.4 years (95% CI: 18.3 - 67.7 years) at the time of HSCT; 68.6% were male. Median follow-up was 4.8 years (95% CI: 3.7 - 5.9 years). Recipients were predominantly European (99 pts), 38 pts were of Asian ethnicity. High PINK scores at diagnosis were reported for 67.8%; 32.2% had low/intermediate PINK scores. Two or more treatment lines had been applied in 79.5% of cases prior to HSCT. Importantly, 73.5% of our pts had received ASP-containing regimens prior to HSCT. Autologous transplantation prior to HSCT had been performed in 21.9% of cases. Remission status at the time of HSCT was complete remission (CR) in 53.7%, partial remission (PR) in 26.5%, and chemorefractory/progressive disease in 12.5%. Reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) were used in 46.7% and 53.3% of cases, respectively. The 1-year and 3-year progression-free survival (PFS) rate for all pts on the study was 55.5% (95% CI: 46.6 - 63.6%) and 48.6% (95% CI: 39.7 - 57%), respectively. The corresponding overall survival (OS) rates were 66.6% (95% CI: 58 - 73.9%) and 55.6% (95% CI: 46.5 - 63.7%), respectively. The cumulative incidence of non-relapse mortality (NRM) at 1 year and 3 years was 15.3% (95% CI: 9.7 - 22.1%) and 17.8% (95% CI: 11.8 - 24.9%) with a relapse incidence (RI) of 29.1% (95% CI: 21.6 - 37.1%) and 33.5% (95% CI: 25.4 - 41.8%) at 1 year and 3 years, respectively. Of note, no relapse was noted beyond 3 years after HSCT. In univariate analyses, ethnicity (European vs. Asian) did not significantly influence PFS (p=0.57), OS (p=0.57), NRM (p=0.79) or RI (p=0.65). Among patients receiving RIC vs. MAC regimens, the relapse incidence (p=0.29) and NRM (p=0.20) were not significantly different. For haploidentical (n=27 pts) vs. HLA-matched related and unrelated donors, no significant differences in terms of PFS (39% (95% CI: 20.2 - 57.4%) vs. 51% (95% CI: 40.9 - 60.2%)), OS (52.6% (95% CI: 31.5 - 70%) vs. 56.1% (95% CI: 46 - 65.1%)), NRM (20.3 (95% CI: 7.1 - 38.3%) vs. 17.3% (95% CI: 10.7 - 25.2%)) and RI (40.7% (95% CI: 21 - 59.6%) vs. 31.7% (95% CI: 22.9 - 40.8%)) at 3 years were observed. For the group of ASP-pretreated patients, 3 year PFS, OS, RI and NRM were 42.4% (95% CI: 32.1 - 52.2%), 52.2% (95% CI: 41.5 - 61.8%), 39.6% (29.5 - 49.5%) and 18.1% (95% CI: 11 - 26.6%), respectively. PD-1 treatment prior to HSCT was applied in 13 patients; these pts did not show significant differences in PFS or OS as compared to all other pts. We also did not observe an increased risk for NRM or acute/chronic GvHD in these pts. Conclusions In a large cohort of Asian and European pts, we demonstrate that HSCT is an effective treatment approach for advanced ENKTL with almost half of the pts achieving long-term survival. These results obtained with the majority of pts having been treated with state-of-the-art ASP-containing therapy prior to transplant compare favorably to previous analyses and show that HSCT is the preferred option for younger pts with ENKTL. PD-1 antibodies given prior to HSCT may help to bring more pts to HSCT without negatively influencing treatment outcomes or GvHD.

Low Toxicity and Disease Responses in Systemic AL-Amyloidosis Using an Yttrium-90 Labelled Anti-CD66 Monoclonal Antibody TLX66 As the Only Conditioning Prior to Autologous Stem Cell Transplantation

Despite the introduction of new therapies Systemic AL-amyloidosis (AL) remains incurable and the majority of patients will relapse. Autologous stem cell transplantation (ASCT) remains an important treatment option with improvement of organ function and survival in responding patients, however the toxicity of ASCT using conventional chemotherapy results in high morbidity and mortality limiting the application in this vulnerable patient group. We tested the use of a monoclonal anti-CD66 radiolabelled with yttrium-90, TLX66 (90Y-besilesomab) as the sole conditioning agent prior to ASCT in a phase I study in patients with AL. The study had full ethical and regulatory approvals (EudraCT 2015-002231-18; ISRCTN 13400668). The study consisted of three radiation activity levels, 30, 40 and 45 Mega Becquerels (MBq) per kg body weight with 3 patients treated at each activity level. Patients entered the study after fulfilling entry requirements and with informed consent. Prior to receiving the 90Y-besilesomab organ dosimetry and biodistribution were determined using the same anti-CD66 radiolabelled with indium-111 (111In-anti-CD66) with sequential gamma camera imaging. Estimated absorbed radiation to critical organs was determined from an established dosimetry model, organ radiation dose expressed in Gray (Gy). Radiation dose limits of 45Gy for the bone marrow and 15Gy for the liver were used as safety measures. Table 1 summarises patient details. The median previous lines of treatment were 2 (range 1-5) including three who had previous ASCT using high dose melphalan. The primary end-point was treatment related toxicity as determined using CTCAE v4.0. Haematological toxicities (cytopenia) were excluded as adverse events (AEs) unless considered life-threatening. Secondary end-points: Disease response determined by changes in clonal free light chain assay (FLCa), malignant plasma cell percentage in BM as determined by multi-colour flow cytometry; cardiac toxicity from NT-proBNP assay; overall survival and time to disease progression; biodistribution and dosimetry SPECT-CT imaging; engraftment using the European Blood and Marrow Transplant (EBMT) criteria for neutrophil and platelet engraftment. Results: Ten patients underwent dosimetry with 111In-anti-CD66, 9 received the 90Y-besilesomabwith infused activity determined by study cohort and patient body weight; one patient failed dosimetry with excessive hepatic uptake, two received reduced activity to keep the marrow dose within the 45Gy limit. There were no serious adverse events (SAE's) in the trial. There were 3 grade 4 AE's (mainly cytopenias during transplantation) and no SUSAR's were reported. A total of 41 grade 1-4 AE's were recorded. There were no transplant related deaths. All patients became profoundly cytopenic consistent with bone marrow suppression due to the targeted radiation. All patients engrafted with median neutrophils recovery by D+13 and platelets by D+11. Importantly, no patients experienced any mucositis or therapy related diarrhoea. All maintained oral nutrition. Only two patients experienced a fever post-transplant, neither were life-threatening. Table 2 summarises the estimated absorbed radiation dose to critical organs and disease responses. Of the 9 patients treated with 90Y-besilesomaband ASCT 7 had haematologic responses with 2 complete responses (CR), 5 partial responses (PR), 1 stable disease (SD) and 1 progressive disease (PD) as determined. Six of 8 evaluable patients showed a reduction in percentage of malignant plasma cells in the BM. The study collected data up to D+100 post-transplant but 2 patients showed continuing slow reduction in clonal FLCa beyond D+100 with 1 achieving a CR 5 months post-transplant. No radiation dose limiting toxicity was seen. No consistent changes were seen in NT-proBNP. Importantly no cardiac AEs were recorded. All patients are alive. The long term follow up data will be presented. Acknowledgement: The native anti CD66 MAb (Besilesomab) was provided by Telix Pharmaceuticals. TLX66 (90Y-besilesomab) was acquired by Telix Pharmaceuticals in 2021. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rituximab Maintenance (RM) after First-Line (1L) Treatment Is Associated with a Lower Risk of Early-POD in Patients with Mantle Cell Lymphoma (MCL)

Background RM after 1L immunochemotherapy has improved the Progression-Free Survival (PFS) and Overall Survival (OS) in MCL in phase III clinical trials and in real-life patients. Early progression/relapse (E-POD) after 1L has been significantly associated with a shorter OS in younger patients with MCL after intensive 1L and autologous stem-cell transplantation (ASCT), although these patients did not receive RM (Visco et al, BJH 2019). The aim of our study was to analyze the impact of the use of RM on the risk of early-POD in a real-life cohort of patients with MCL. Methods We retrospectively reviewed all patients diagnosed with MCL between January 2000 and December 2021 at 6 tertiary centers. Only patients receiving 1L at diagnosis and achieving complete (CR) or partial response (PR) were eligible for maintenance and therefore included in this analysis. Patients were categorized as "RM” if they had received RM after 1L or as "non-RM” if they had not. Relapse/progression after 1L occurring before or after the first 24 months (m) from diagnosis was considered early or E-POD and late or L-POD, respectively (Visco et al, BJH 2019). Patients not relapsing after 1L were considered L-POD only if their follow-up time (FU) from diagnosis was 24 months or longer. Patient's characteristics, biological risk factors at diagnosis, as well as the type of 1L were recorded (intensive immunochemotherapy with high-dose cytarabine -HiDAC- or standard immunochemotherapy without HiDAC -non-HiDAC-), with or without ASCT consolidation. The duration of response (DOR) after 1L, PFS and OS were also analyzed for all patients. Statistical analyses were performed with the R-4.1.0 software. Univariate logistic regression was carried out to study the association between E-POD and maintenance. Survival analysis (DOR, PFS and OS) were calculated using the Kaplan-Meier method and the univariate Cox was used for statistical comparison. Results Out of 212 patients attaining CR or PR after 1L, 87 (41%) received maintenance therapy (RM group) whereas 125 patients (59%) did not (non-RM group). The RM regimens administered were: rituximab monotherapy (R)/8 weeks (wk) x 2 years (N=41), R/8 wk x 3 years (N=27) and other R-based regimens (with BTK inhibitors, N=7; other R schedules, N=12). Except for a higher percentage of patients older >65 years at diagnosis in the RM group (51.7% RM vs. 37.6% non-RM, p=0.042), the rest of baseline characteristics were well balanced between the two groups (Table 1). Regarding 1L, more patients in the full cohort had received a non-HiDAC regimen [120 pts (56.6%) non-HiDAC vs. 92 pts (43.4%) HiDAC], but the proportion of patients receiving RM was similar after both types of 1L. Only 22 out of the 87 patients in the RM group (25.3%) had undergone previous ASCT consolidation (Table 1). With a median follow-up of 72.8 months (51.52 m and 92.65 m in the RM and non-RM groups, respectively), median PFS was 44.39 m (36.11-55.46), with a significant advantage for the RM group (61.04 m vs. 32.82 m, HR=1.7 [1.15-2.51], p=0.01) (Figure 1). Moreover, median DOR was 30.03 m (26.02-42.94), also significantly longer in the RM group (53.88 m vs. 24.21 m, HR=1.61 [1.12-2.3], p=0.01). Median OS was 12.18 yrs (8.66-NR) in the full cohort, with no significant differences between the two groups (14.03 yrs vs. 11.48 yrs, HR=1.34 [0.74-2.45], p=0.34). Regarding POD24, a statistically significant association was observed between not receiving RM and early-POD: 49 patients (40.5%) were E-POD in the non-RM group compared with only 19 (24.4%) in the RM group (OR=2.11 [1.14-4.04], p=0.020) (Table 1). Conclusions Only 41% of our real-life cohort received RM despite it being considered a safe and effective strategy for MCL patients. In line with previous studies, in our series RM after 1L is associated with a significant advantage in terms of PFS and DOR, although it did not have impact on OS. In our cohort, RM is significantly associated with a lower risk of early-POD, in all age groups and regardless of the 1L induction strategy, therefore confirming the benefit of this strategy in the management and outcomes of MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Timely Leukapheresis May Interfere with the "Fitness" of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients.

The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematological diseases. However, approximately 60% of patients relapse after CAR-T cell therapy, and no clear cause for this failure has been identified. The objective of the Bio-CAR-T BS study (ClinicalTrials.gov: NCT05366569) is to improve our understanding of the lymphocyte harvest to maximize the quality of the CAR-T cell product. Of the 14 patients enrolled, 11 were diagnosed with DLBCL, 2 with PMBCL, and 1 with ALL. Five of 11 DLBCL patients met the criteria for "pre-emptive" Lymphocytes-apheresis (being at high risk of second relapse), and 6 were included in the standard-of-care Lymphocytes-apheresis group. Previous autologous stem cell transplantation (ASCT) and age were significantly different between the two groups. At the time of Lymphocyte-apheresis, patients in the "pre-emptive" group had more "fit" lymphocytes (higher CD4+/CD8+ ratio; higher naïve T cells levels) compared with standard group, probably due to the impact of ASCT. At the same time, also being older than 60 years results in a more "exhausted" lymphocyte profile. Overall, "pre-emptive" Ly-apheresis in DLBCL patients at high risk of relapse appears to be feasible and may allow the timely collection of "fit" lymphocytes for CAR-T cell manufacturing.

Paraskeletal and extramedullary plasmacytomas in multiple myeloma at diagnosis and at first relapse: 50-years of experience from an academic institution

From January 1970 to December 2018, 1304 patients were diagnosed with multiple myeloma (MM) at our institution and 256 (19.6%) had plasmacytomas (Ps) (paraskeletal –PPs- 17.6%, extramedullary –EMPs-1.9%). Patients with Ps had lower serum M-protein and less advanced ISS stage than those without. At first relapse, 192 out of 967 patients (19.8%) developed Ps (PPs 14.6%, EMPs 5.1%). The only factor associated with Ps at relapse was the presence of Ps at diagnosis (46% vs 13%, p < 0.00001) with no impact with exposure to novel drugs or previous autologous stem-cell transplantation (ASCT). The median overall survival (OS) was 45, 44 and 20 months for patients without Ps, PPs and EMPs, respectively (p = 0.013). Patients with PPs who underwent ASCT had similar OS than those without Ps (98 vs. 113 months) and significantly longer than those with EMPs (98 vs 47 months, p = 0.006). In patients non-eligible for ASCT the presence of PPs or EMPs was associated with shorter OS compared with patients without Ps (32 vs. 24 vs. 6 months, p = 0.009). In the relapsed setting, a significant survival benefit was observed beyond the year 2000, but still with significant differences among patients without Ps, PPs and EMPs (37 vs 22 vs 16 months, p = 0.003). Importantly, rescue therapy with combinations of proteasome-inhibitors plus immunomodulatory drugs was associated with prolonged OS from first relapse (over 6 years), even in patients with EMPs.

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Real-World Patterns of Utilization and Outcome of Market Approved Lenalidomide-Based Triplet Combinations in First Relapsed Multiple Myeloma Patients: Evidence from a Propensity Score Matched Analysis

Background: Lenalidomide (R) plus dexamethasone (d) triplet combinations have been indicated by ESMO guidelines as standard of care in first relapse for lenalidomide sensitive multiple myeloma (MM) patients (pts) (Dimopoulos et al, 2021). Meta-analysis of randomized clinical trials (RCT) shows better outcome with the combination of Daratumumab + Rd (DaraRd) over other Rd-based combinations (carfilzomib+Rd (KRd), elotuzumab+Rd (EloRd), Ixazomib+Rd (IxaRd). There are few real-life studies focusing on the pattern of utilization and outcome of different Rd triplets in first relapse MM.Aims: To explore performances of market-approved Rd-based triplets in unselected MM pts in first relapse.Patients and methods: After ethics committee approval, we review data of 366 MM pts in first relapse consecutively addressed to Rd-based triplets according to market-approved schedule after 2017. Rd-based therapies was distributed as follows: DaraRd 51.6% (189 pts), KRd 36.1% (132 pts), EloRd 8.7% (32 pts), IxaRd 3.6% (13 pts). Given the limited number of pts treated with IRd and EloRd, the analysis is focused only on DaraRd and KRd group after further excluding 51 pts (13%) addressed to salvage autologous stem cell transplant (ASCT) after daraRd (n=9)/KRd(n=42) fixed induction. Few pts in both groups were previously exposed to R/K/Dara (respectively 12 pts (3%), 8 (2%), 0). Treatment choice was influenced by market approval, with KRD regimen used more commonly in the IQR 2017- 2019, while DaraRd more commonly in the IQR 2018-2020. To limit the bias of a retrospective observation, we calculated a propensity score and we used it (after trimming of 5% of observations) to re-weight the data, according to the Inverse Probability of Treatment method (IPTW analysis). For the estimation of the propensity score, we used: age at Rd-triplet starting, ISS stage, presence of high-risk FISH, previous exposure to Bortezomib, previous ASCT, good response at first-line therapy (≥VGPR), time between diagnosis and relapse, myeloma defining events at diagnosis, type of relapse (symptomatic/biochemical), center. Details of these characteristics are reported in table1. Of note, pts addressed to DaraRd were slightly older (68,7 vs 63,4 years in KRd, p<0.001), time from diagnosis was quite longer (3,5 vs 2,9 year in KRd, p=0.094), they received a lower rate of prior ASCT (56% vs 72% in KRd, p=0.008). After a median follow-up of 21.6 months (IQR: 9.6-32.4), response rate ≥PR were similar in both groups (92% in DaraRd vs 87,6% in KRd, IPTW analysis: OR=0.8, 95%CI: 0.4-1.5, p=0.422). No significant difference was found in terms of ≥VGPR (60% in DaraRd vs 62,9% in KRd, IPTW analysis: OR=0.7, 95%CI: 0,4-1,1 p=0.098) as well as of ≥CR (16,6% in DaraRd and 23,6% in KRd, IPTW analysis: OR=1,3, 95%CI: 0.8-2,2, p=0.340). The median number of administered cycles was higher for DaraRd (12 vs 10, IPTW analysis: β: 0.2, 95%CI: 0.1-0.4, p=0.025). Discontinuation rate was lower with DaraRd (28% vs 62% with KRd, IPTW analysis: OR: 0.3, 95%CI: 0.2-0.4, p<0.001). Most patients in both groups discontinued treatment for progression (55,3% with DaraRd and 59.3% with KRd), discontinuation for TEAE was reported respectively in 38,3% in DaraRd and 31,5% in KR; 6,4% of pts in DaraRd and 9,2% in KRd discontinued treatment for pts decision. Weighted analysis shows a similar outcome. In particular, the median PFS is 28 months for DaraRd vs 23 months for KRd, (HR=0.9, 95%CI: 0.6-1.2, p=0,420) (Figure 1). At left-truncation analysis, patients with ≥VGPR, had similar PFS when comparing DaraRd vs KRd (HR=1.0, 95%CI: 0.6-1.6, p=0.896) while in patients with ≤PR, DaraRd showed a longer PFS (HR=0.5, 95%CI: 0.3-0.9, p=0.012) (Figure 2). The median TTNT was 31 and 29 months in DaraRd and KRd, respectively (HR=0.8, 95%CI: 0.5-1,1 p=0,111). No difference was found in terms of OS (HR=1.2, 95%CI: 0.8-1.8, p=0.408)(Figure 3).Conclusions: Our real-life study shows that DaraRd represents the most commonly received regimen at first relapse followed by KRd triplet. After propensity score matching, DaraRd and KRd combinations proved to be both effective with similar outcomes when used early in the treatment history, after one line of therapy. This study, in addition, points out the possible gap of outcome between RCT and clinical practice. [Display omitted] DisclosuresMangiacavalli: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Fazio: Janseen: Honoraria. Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board.

Safety and Efficacy Profile of Autologous CD30.CAR-T-Cell Therapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (CHARIOT Trial)

Safety and Efficacy Profile of Autologous CD30.CAR-T-Cell Therapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (CHARIOT Trial)

Single Agent Daratumumab in Advanced Multiple Myeloma: Specific Healthcare Program in the Czech Republic

Aims: The introduction of anti-CD38 antibody daratumumab (DARA) into the treatment of multiple myeloma (MM) has significantly changed recent view on the approach to this disease. The drug was approved by FDA based on phase II clinical trial (SIRIUS) with breakthrough results in advanced multiple myeloma even as a monotherapy. Recent updates on combined regimens with bortezomib or lenalidomide and dexamethasone (clinical trials CASTOR and POLLUX) in relapsed MM have an unpreceded therapeutic effect as well as survival measures, so that DARA is reckoned as the future backbone of MM treatment. We present our first experience with single agent DARA in advanced MM within the Specific Healthcare Program.Patients and Methods: The Specific Healthcare Program was introduced in order to assess the effect of DARA in real world setting, and to faciliate the access to the drug to patients before the approval by European Medicines Agency (EMA). The program offered single agent DARA treatment to 14 patients with MM based on the FDA registration conditions, i.e. for patients who have received three or more prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent. The patients were with 1:1 male to female ratio, with median age 60,7 years (37-80 years). The patients were treated with single agent DARA 16mg/kg i.v. per week for 8 weeks, then every 2 weeks for 16 weeks, and every 4 weeks thereafter. We assessed the pre-treatment of the patients, prognostic factors (cytogenetics and presence of extramedullary disease) with regard to response rates, evidence of adverse events and survival measures using progression free survival (PFS) and overall survival (OS).Results: The patients had median 4,5 previous treatment lines (2-8). Overall, 93% of the patients had previous autologous stem cell transplant, 100% of them received bortezomib, 21% carfilzomib, 64% thalidomide, 86% lenalidomide and 50% pomalidomide. Extramedullary disease was found in 21% (3 out of 14), cytogenetic profile revealed t(4;14) in 5 out of 7 patients, del17 in 1 out of 6 patients, del13 in 7 out of 8 patients, amp1q21 in 3 out of 6 patients, the rest was not assessed for specific cytogenetic changes at the time before DARA treatment. The cohort (9 assessable responses) reached overall response rate (ORR) in 33% with 11,1% very good partial remissions (VGPR), 22,2% of partial remissions (PR), stable disease (SD) was in 11,1% and progression (PG) in 55,6%. The toxicities were recorded in 5 patients only, and were mostly grade I or II: weakness and fatigue, anemia, neutropenia, nausea and vomiting and anorexia. Only infection and thrombocytopenia reached grade III (in 60% and 20% respectively), and one patient had grade IV infectious complications. The median progression free survival of the cohort was 4,6 months and median overall survival was not reached with median follow-up 7,2 months.Conclusions: The results of single agent daratumumab in our real world cohort are very similar to those reported in SIRIUS trial. The treatment is feasible, accompanied only with minor toxicities, and has a substantial treatment response even in heavily pretreated population in advanced multiple myeloma.With support of IGA-LF-2017-007, AZV 17-29343A. DisclosuresSpicka:Celgene: Research Funding; Celgene, Amgen, BMS, Janssen, Takeda, Sanofi: Honoraria; Celgene, Amgen, BMS, Janssen, Takeda, Sanofi, Pharmamar: Speakers Bureau. Hájek:Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria.

A Phase II Study of a Novel Conditioning Regimen of Bendamustine and Melphalan Followed By Autologous Stem Cell Transplant for Patients with Multiple Myeloma

IntroductionHigh dose melphalan 200mg/m2 (MEL200) followed by autologous stem cell transplantation (ASCT) is the standard of care for fit patients with Multiple Myeloma (MM). Bendamustine has been shown to induce responses in MM resistant to other alkylating agents. Our prior Phase I trial, adding bendamustine to MEL200, demonstrated no additional toxicity above that expected with MEL200 alone (Mark et. al. BBMT 2013). A phase 2 trial of bendamustine/MEL200 conditioning was conducted to evaluate treatment efficacy.Objective and MethodsThis single arm, open-label, phase II study was designed to establish the efficacy of Bendamustine (225 mg/m2) in combination with MEL200 in patients undergoing first ASCT for MM. Patients 18 to 75 years with confirmed MM, prior induction therapy, adequate mobilization (at least 2x106 of CD34+ hematopoietic stem cells), Karnofsky performance status >70% and life expectancy >12 weeks were eligible for screening. Major exclusion criteria included serious/uncontrolled medical conditions, or previous ASCT. Responses were determined according to the IMWG response criteria and adverse events (AEs) were reported per CTCAEv4.0. The primary endpoint was to evaluate the overall response rate (ORR) and CR or better at 6 months.ResultsA total of 35 patients were enrolled (Table 1). Median age was 61 (range 41 - 75). Intermediate or high-risk disease was present in 44.8% by R-ISS. All patients engrafted. Median time to neutrophil and platelet engraftment was 11 days (range 10-14) and 21 days (range 15 to 29) respectively. At day +180, the ORR was 91.4% and 51.4% of patients achieved a CR or sCR (Table 2). Only 1 patient progressed before day +100 (R-ISS 1 double-refractory to lenalidomide + bortezomib, achieved VGPR with second line therapy with VDT-PACE prior to transplant), and one additional patient progressed before Day +180 (R-ISS 2, with prior 4 lines of therapy, SD prior to transplant). Maintenance was initiated in 20 patients out of 32 patients (62.5%). Choice of maintenance was at the discretion of the treating physician and patient.After a median 33 months (range 3-73) of follow up post ASCT, 20 patients had progressed (57.1%), 4 of whom died from complications of MM progression (11.4%). Median progression free survival (PFS) was 40 months (14 months vs 48 months depending on maintenance therapy, p=0.024). The 3 year PFS was 64.5% (95%CI 44.7-78.8). The median overall survival (OS) was not reached. The 3 year OS was 91.2% (95%CI 75.1-97.1) (Figure 1). Baseline response, categorized as CR or better, VGPR, PR and SD or PD prior to transplant, was statistically significant for PFS (p=0.019). In a multivariable Cox proportional hazards model controlling for baseline response prior to transplant, maintenance therapy continued to be associated with improved PFS (HR 0.16, p=0.004). No variable had a statistically significant impact on OS. There was no transplant related mortality (TRM). The most common overall AEs were hypocalcemia (100%), nausea (94.3%), fatigue (94.3%), anorexia (91.4%), mucositis (57.1%), abdominal pain (51.4%), peripheral edema (48.6%) and constipation (34.7%). The most frequently observed grade 3 AEs were febrile neutropenia in 45.7% of patients, hypocalcaemia in 34.3%, hypokalemia in 20%, and hypophosphatemia in 14.3%. There was only one grade 4 AE, hyperbilirubinemia associated with a reaction to antibiotics.ConclusionWe confirmed that Bendamustine can safely be combined with standard dose MEL200 as a conditioning regimen for ASCT. This regimen shows promising efficacy, with median PFS of 48 months for patients who received maintenance. Further evaluation of this conditioning regimen in a Phase III comparison trial with single agent MEL200 is warranted in conjunction with newer induction approaches and standard maintenance therapies. (NCT00916058). [Display omitted] DisclosuresNiesvizky:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Rossi:Celgene: Consultancy; Thrassos: Consultancy.

A retrospective study of efficacy and safety of mechlorethamine, vindesine, liposomal doxorubicin, and prednisone (MODP) in relapsed/refractory classical Hodgkin lymphoma.

e19516 Background: There are few optimized therapeutic options for relapsed and/or refractory classic Hodgkin’s lymphoma (r/rCHL), especially in patients who failed in treatments of autologous stem cell transplantation (ASCT), brentuximab vedotin or even immune checkpoint blockage. Therefore, we developed a chemotherapeutic scheme to evaluate the efficacy in r/rCHL patients with previous various lines of therapies. Methods: Between January, 2014 and December, 2019, a retrospective study was performed on r/rCHL patients from Chinese PLA general hospital who were treated with MOAP regimen consisting of mechlorethamine 6mg/m2, vindesine 4mg, liposomal doxorubicin 15mg/m2 on days 1 and 8, prednisone 1mg/kg per day on days 1 to 10 (MOAP) every 4 weeks. CT or PET/CT were done every two cycles to assess the response. Patients treated with MOAP regimen and complete clinical data were included. Patients with less than two cycles of MOAT or unavailable response assessment were excluded. The primary endpoint were complete remission (CR) and progression-free survival (PFS). Results: A total of 87 patients were included and five patients were excluded, so 82 patients were eligible in the study. The median previous lines and cycles of chemotherapy was 2 (range, 1-7), and 9 (range, 3-31), respectively. All the eligible patients received MOAP regimen for a median 4 cycles (range from 2 to 8), and overall response rate (ORR) was 87.8% including 40 patients in CR (48.8%) and 32 in PR (39.0%). In patients with ≥ 3 lines or ≥ 10 cycles of chemotherapy, up to 50.0% and 41.0% of patients achieved CR, respectively. In patients with previous ASCT, 31.6% of patients also achieved CR. Patients with previous checkpoint inhibitors had even higher CR than those without checkpoint inhibitors, though not significantly (51.6% vs. 47.1%, p = 0.689). Median PFS in patients with CR, PR and SD/PD were 43.8 months, 9.6 months and 6.1 months, respectively (p = 0.000).Patients with &lt; 3 previous lines of chemotherapy had a favorable PFS than those with ≥ 3 previous lines (not reached vs. 14.4 months, (p = 0.032). No differences in PFS were observed in terms of previous cycles of chemotherapy, ASCT and checkpoint inhibitors. Grade ≥ 3 adverse events included 37 leukopenia (45.1%), 16 lung infection (19.5%), 11 anemia (13.4%), 4 thrombocytopenia (4.9%), 3 febrile neutropenia (3.7%) and 3 increased transaminase (3.7%). Conclusions: The MOAP combination regimen produced a favorable CR in r/rCHL failing or progressing on ASCT, checkpoint inhibitors, multiple cycles or lines of chemotherapies. It is an effective salvage regimen in heavily pretreated r/r CHL.