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PURPOSE Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)–positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

TPS1106 Background: Immune checkpoint inhibitors (ICIs) have not yet benefited most patients with breast cancer. In mTNBC, ICIs combined with chemotherapy have improved survival only in PD-L1+ mTNBC. The optimal ICI combination agent to overcome primary resistance in PD-L1– mTNBC is unknown. One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.6 months in mTNBC with ≥2 prior lines of chemotherapy.1 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity.2 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models.3 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors,4 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors. Methods: This is a multi-center 1:1 randomized phase II trial to investigate whether the addition of pembrolizumab (200 mg IV every 3 weeks) to SG (10 mg/kg IV days 1+8 every 21 days) improves PFS compared to SG alone in mTNBC that is PD-L1– by standard of care testing with 22C3 CPS < 10 or SP142 immune cells < 1% (NCT04468061). Key eligibility criteria include no prior systemic therapy for mTNBC and evaluable disease. Previously treated brain metastases are permitted. Exclusion criteria include prior treatment with SG, irinotecan, and PD-1/L1 inhibitors. Based on a sample size of 110 patients per arm, the trial has 80% power to detect a 3-month difference in median PFS from 5.5 months in the SG-alone cohort to 8.5 months in the SG + pembrolizumab cohort with a one-sided alpha of 0.1. Participants undergo mandatory baseline and on-treatment research biopsies if their disease is safely accessible. Tumor biopsies will be evaluated for Trop-2, immune cells, inhibitory checkpoints, transcriptomic signatures, and genomic alterations. Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed. The trial is currently open and enrolling patients. References: 1) Bardia A et al. Ann Oncol 31, S1142-S1215 (2020). 2) Cardillo TM et al. Bioconjug Chem 26, 919-931 (2015). 3) Iwai T et al. Oncotarget 9, 31411-31421 (2018). 4) Hibino S et al. Cancer Res 78, 3027-3040 (2018). Clinical trial information: NCT04468061 .

Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 × 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rosefivefold (P.001) andfourfold (P.001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rosefivefold (P.001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg:Tcon ratios ≥0.07 at baseline and ≥0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated.

Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell–replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.)

The lacZ reversion assay in Escherichia coli measures point mutations that occur by specific base substitutions and frameshift mutations. The tester strains cannot use lactose as a carbon source (Lac(-)), and revertants are easily detected by growth on lactose medium (Lac(+)). Six strains identify the six possible base substitutions, and five strains measure +G, -G, -CG, +A and -A frameshifts. Strong mutagens give dose-dependent increases in numbers of revertants per plate and revertant frequencies. Testing compounds that are arguably nonmutagens or weakly mutagenic, we often noted statistically significant dose-dependent increases in revertant frequency that were not accompanied by an absolute increase in numbers of revertants. The increase in frequency was wholly ascribable to a declining number of viable cells owing to toxicity. Analysis of the conditions revealed that the frequency of spontaneous revertants is higher when there are fewer viable cells per plate. The phenomenon resembles "adaptive" or "stress" mutagenesis, whereby lactose revertants accumulate in Lac(-) bacteria under starvation conditions in the absence of catabolite repression. Adaptive mutation is observed after long incubation and might be expected to be irrelevant in a standard assay using 48-h incubation. However, we found that elevated revertant frequencies occur under typical assay conditions when the bacterial lawn is thin, and this can cause increases in revertant frequency that mimic chemical mutagenesis when treatments are toxic but not mutagenic. Responses that resemble chemical mutagenesis were observed in the absence of mutagenic treatment in strains that revert by different frameshift mutations. The magnitude of the artifact is affected by cell density, dilution, culture age, incubation time, catabolite repression and the age and composition of media. Although the specific reversion assay is effective for quickly distinguishing classes of mutations induced by potent mutagens, its utility for discerning effects of weak mutagens may be compromised by the artifact.

Aprior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after human leukocyte antigen (HLA)-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft-versus-host disease incidence, with promising overall and progression-free survival. We performed an open-label three-arm 1:1:1 phase II randomized controlled trial comparing grade II-IV acute graft-versus-host disease between conventional tacrolimus/methotrexate (A) versus bortezomib/tacrolimus/methotrexate (B), and versus bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors. The primary endpoint was grade II-IV acute graft-versus-host disease incidence rate by day +180. One hundred and thirty-eight patients (A 46, B 45, C 47) with a median age of 64 years (range: 24-75), varying malignant diagnoses and disease risk (low 14, intermediate 96, high/very high 28) received 7-8/8 HLA-mismatched (40) or matched unrelated donor (98) grafts. Median follow up in survivors was 30 months (range: 14-46). Despite early immune reconstitution differences, day +180 grade II-IV acute graft-versus-host disease rates were similar (A 32.6%, B 31.1%, C 21%; P=0.53 for A vs B, P=0.16 for A vs C). The 2-year non-relapse mortality incidence was similar (A 14%, B 16%, C 6.4%; P=0.62), as were relapse (A 32%, B 32%, C 38%; P=0.74), chronic graft-versus-host disease (A 59%, B 60% C 55%; P=0.66), progression-free survival (A 54%, B 52%, C 55%; P=0.95), and overall survival (A 61%, B 62%, C 62%; P=0.98). Overall, the bortezomib-based regimens evaluated did not improve outcomes compared with tacrolimus/methotrexate therapy. clinicaltrials.gov Identifier: 01754389.

Background: Single-agent platinum compounds have significant clinical activity in the neoadjuvant and metastatic settings for triple-negative breast cancer (TNBC) in BRCA mutation carriers. Limited data exist regarding activity in estrogen receptor (ER)-positive breast cancer among BRCA carriers. The INFORM trial is an investigator-initiated, randomized, multicenter, phase II study comparing pathologic complete response (pCR) rates with neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin/cyclophosphamide (AC) in BRCA carriers with newly-diagnosed Stage I-III HER2-negative breast cancer. Methods: BRCA carriers with cT1-3 (≥1.5 cm), cN0-3 HER2-negative breast cancer were randomized (stratified by site and ER status) 1:1 to preoperative CDDP (75mg/m2 every 3 wks x 4) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 wks x 4) followed by surgery. Prior chemotherapy was not allowed; subsequent adjuvant therapy was selected by treating clinicians. Baseline tumor features and pathologic responses were centrally determined. The primary endpoint was pCR (ypT0/is, N0). Based on a 2-sided α=0.1, a sample size of 170 provided 80% power to detect an improvement in pCR from 30% with AC to 50% with CDDP. Slow accrual led to early trial closure. We used an intent-to-treat approach and log-binomial regression to calculate risk ratios (95% confidence intervals (CI)), adjusting for ER status. Results: We randomized 118 patients; 117 were included in outcome analyses. The mean age was 42 years (range: 24-73); 69% were BRCA1+, 30% BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% of patients had nodal involvement at baseline. Most patients (70%) had TNBC (ER/PR Table 1: Intention-to-treat analysis comparing CDDP to ACCDDP n=60 n (%)AC* n=57 n (%)Crude Risk Ratio (95% CI)Adjusted Risk Ratio§ (95% CI)Pathologic complete responseResidual cancer burden score: 0All participants11 (18)15 (26)0.70 (0.35-1.4)0.67 (0.35-1.3)Triple negative (ER and PR Conclusion: While CDDP has single-agent activity in BRCA carriers with HER2-negative breast cancer, the pCR rate with CDDP is not higher than with standard AC chemotherapy. CDDP activity was notably lower in BRCA carriers with hormone-receptor positive breast cancer, though the sample size was small. Study-collected tumor and blood samples are being analyzed for biomarkers of response. Clinical information: NCT01670500. Funding: Breast Cancer Research Foundation; Susan G. Komen for the Cure; Myriad Genetics, Inc. Citation Format: Nadine Tung, Banu Arun, Erin Hofstatter, Michele R. Hacker, Deborah L. Toppmeyer, Steven J. Isakoff, Virginia Borges, Robert D. Legare, Claudine Isaacs, Antonio C. Wolff, Paul K. Marcom, Erica L. Mayer, Paulina B. Lange, Andrew J. Goss, Ian E. Krop, Eric P. Winer, Stuart J. Schnitt, Judy E. Garber. Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-03.

TPS1115 Background: A previous study from our group showed that approximately 9% of metastatic breast cancer (MBC) is hypermutated, defined as a tumor mutational burden (TMB) ≥10 Mutations/Megabase (Mut/Mb). The aim of this study is to evaluate if patients with hypermutated HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/Kg intravenously (IV) every 14 days plus Ipilimumab 1 mg/Kg IV every 6 weeks in subjects with hypermutated metastatic HER2-negative breast cancer. Patients with measurable HER2-negative MBC, TMB ≥10 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting are eligible. The primary objective is overall response rate according to RECIST 1.1. Secondary objectives include the safety and tolerability of the combination, progression-free survival, and overall survival. The study will follow a two-stage design. In the first stage 14 patients will be enrolled. If there is at least one patient with objective response, accrual will continue to the second stage where an additional 16 patients will be enrolled. If there are at least 4 patients with an objective response among the 30 patients, the regimen will be considered worthy of further study. If the true response rate is 5%, the chance the regimen is declared worthy of further study is less than 5%. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is > 90%. Tumor biopsies, peripheral blood, and stool collection are mandatory and will be obtained at baseline, on treatment (end of cycle 1), and at disease progression and will be assessed for potential biomarkers of treatment response. The trial was activated in February 2019, and accrual should be completed in 18 months. Clinical trial information: NCT03789110.

Inhibition of the mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-i.v. acute GVHD (9% versus 25%, p=0.015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

Background: We previously reported on a novel bortezomib (bort)/tacrolimus(tac)/methotrexate (mtx) regimen with low rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) and promising overall and progression-free survival (OS, PFS) in HLA-mismatched donor (MMD) reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT). To determine whether bort provided a meaningful improvement in outcomes, we undertook a prospective randomized controlled trial (RCT) of standard-of-care (SOC) tac/mtx versus 2 novel bortezomib-based GVHD regimens for RIC HSCT recipients lacking HLA-matched related donors (Clinical Trial ID: NCT01754389). Intervention: The open-label phase II 3-arm 1:1:1 RCT enrolled adult hematologic malignancy patients aged 18-75 years. Conditioning was IV busulfan (0.8 mg/kg BID) and fludarabine (30 mg/m2 QD) from d-5 to -2. 8/8 matched unrelated donor (MUD) or 7/8 MMD T-replete PBSC grafts (≥ 2x106 CD34+ cells/kg) were infused on d0. GVHD regimens were: tac/mtx (arm A, SOC); bort/tac/mtx (arm B); and bort /sirolimus (siro)/tac (arm C) dosed as: bort (1.3 mg/m2 IV d+1, +4, +7), mtx (10 mg/m2 IV d+1, 5 mg/m2 d+3, +6, +11), siro (target trough level 5-12 ng/ml) and/or tac (target trough level 5-10 ng/ml) from d-3 with taper from d+100 and complete by d+180, as applicable per treatment arm. Primary endpoint was grade II-IV acute GVHD incidence by d+180. Secondary endpoints included NRM, relapse, PFS, OS and chronic GVHD at 1 year. Patient and transplant variables: 138 evaluable patients with a median age of 64 years (range, 24-75), variable diagnoses (53 AML, 33 MDS, 20 NHL, 11 CLL, etc) and disease-risk indices (Low 14, Intermediate 96, High/Very High 28) were accrued between Jan 2013 and Nov 2015. They received 8/8 (98) MUD or 7/8 (40) MMD PBSC grafts. The treatment arms (A: 46; B: 45; C: 47) were balanced for pre-transplant variables, except for lower CMV seropositivity in arm C (78.3% vs. 77.8% vs. 53.2%, p=0.01). Median follow up in survivors was 15 months (range, 5.5-38). Outcomes: The regimens were well tolerated. No bort doses required omission or reduction. Grade 3-5 AE rates were similar across arms. TMA/HUS and VOD rates were not different (p=0.16, p=0.41, respectively). Median day +30 donor chimerism was ~96% (range, 42-100) across arms (p=0.84). The d+180 incidence of grade II-IV acute GVHD was similar overall across arms at 33% (A) vs. 31% (B) vs. 21% (C, p=0.65, Figure 1), but for the 8/8 MUD subgroup it was 33% (A) vs. 16% (B) vs. 19% (C) with a trend to significance for the bort-based regimens at 33% (A) vs. 17% (B+C, p=0.08). Across arms, the 1-year NRM incidence was 11% (A) vs. 15% (B) vs. 6.5% (C, p=0.43), and relapse was 24% (A) vs. 28% (B) vs. 36% (C, p=0.62). The 1-year incidence of extensive chronic GVHD was 39% (A) vs. 44% (B) vs. 48% (C, p=0.52). 1-year PFS was 64% (A) vs. 57% (B) vs. 57% (C, p=0.89, Figure 2), and OS was 72% (A) vs. 63% (B) vs. 70% (C, p=0.54). Conclusions: 1. For 7/8 MMD RIC HSCT, adding bort does not provide benefit to SOC tac/mtx, which offers outcomes better than historically anticipated. 2. For 8/8 MUD RIC HSCT, adding bort may offer grade II-IV acute GVHD benefit, but direct randomization with an appropriately powered sample size would be required for confirmation. Disclosures Koreth: kadmon corp: Membership on an entity's Board of Directors or advisory committees; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; amgen inc: Consultancy; LLS: Research Funding; millennium pharmaceuticals: Research Funding. Armand:Roche: Research Funding; Pfizer: Research Funding; Merck: Consultancy, Research Funding; Sequenta Inc: Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees.

In a phase I/II trial of a novel bortezomib-based regimen for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) recipients of HLA-mismatched peripheral blood stem cell (PBSC) grafts, we documented low rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM), with promising survival. In registry analyses, myeloablative conditioning (MAC) HSCT recipients of both HLA-matched (MUD) and 1-locus mismatched donor (MMUD) grafts also have impaired outcomes, with day +100 grade III-IV acute GVHD rates of 28% and 37% respectively, 1-year NRM of 36% and 45% respectively, 1-year progression-free (PFS) of 47% and 38% respectively, and 1-year overall survival (OS) of 52% and 43% respectively. We therefore evaluated a similar bortezomib-based regimen in MAC HSCT recipients lacking 8/8 HLA-matched (-A, -B, -C, -DRB1) related donors. In a prospective single-arm phase II trial, we enrolled patients with hematologic malignancies, aged 18-60 years, receiving MUD, MMUD, or mismatched related donor (MMRD) grafts. Myeloablative conditioning was IV busulfan (130 mg/m2, without PK dose adjustment) and fludarabine (40 mg/m2) once daily for 4 doses (days -7 to -4). T-replete PBSC grafts with ≥ 2x106 CD34+ cells/kg were infused on day 0. GVHD prophylaxis comprised bortezomib (1.3 mg/m2 IV on days +1, +4, +7), methotrexate (15 mg/m2 IV on day +1, 10 mg/m2 on days +3, +6, +11) and tacrolimus from day -3, with a planned taper starting day +100 and complete by day +180. The primary endpoint was day +100 acute GVHD incidence. Secondary endpoints included NRM, relapse, PFS, OS and chronic GVHD at 1 year. The 34 patients (19 male, 15 female), accrued between March 2011 and November 2012, had a median age of 49 years (range, 21-60) and variable diagnoses (17 AML, 6 MDS, 4 NHL, 3 MPD, 2 ALL, 1 CML, 1 MM) and disease risk indices (Low 1, Intermediate 24, High 9). They received 8/8 MUD (n=14), 7/8 MMUD (n=18) or 7/8 MMRD (n=2) PBSC grafts. Mismatches (16 antigen-, 4 allele-level) involved HLA-A (9), -B (1), -C (6) and -DRB1 (4). The median follow up in survivors is 20 months (range, 7.2-25.5). The regimen was feasible and well tolerated. Mucositis was noted in the MAC recipients, but no doses were missed due to toxicity. Excluding 1 patient who died of sepsis prior to engraftment, neutrophil and platelet engraftment was prompt, at a median of 14 (range, 3-33) and 17 (range, 7-54) days respectively. Median day +30 donor chimerism was 99% (range, 90-100). Grade II-IV acute GVHD incidence by day +100 and +180 was 32% and 36% respectively, but only 18% and 21% respectively if upper GI GVHD (which had excellent long term outcomes) was excluded. Grade III-IV acute GVHD incidence by day +100 and +180 was 12%. 2-year cumulative incidence of NRM and relapse was 8.8% and 5.9% respectively. 2-year PFS and OS was 85% and 84% respectively (Figure). 2-year cumulative incidence of extensive chronic GVHD was 57%. For 8/8 MUD vs. 7/8 MMRD/MMUD, grade II-IV acute GVHD by day +180 was 30% vs. 40% (p=0.47) (excluding upper GI GVHD, 16% vs. 25%, p=0.42), and grade III-IV acute GVHD was 7% vs. 15% (p=0.48) respectively.FigureStudy SurvivalFigure. Study Survival In conclusion, bortezomib-based prophylaxis for MAC HSCT recipients of HLA-mismatched and unrelated donor grafts was safe and well-tolerated, with low rates of severe acute GVHD, NRM and relapse, and excellent long-term survival. On preliminary landmark analysis, upper GI GVHD did not appear to impair transplantation outcomes. Bortezomib-based prophylaxis is suitable for prospective randomized evaluation in myeloablative transplantation recipients lacking HLA-matched related donors. Disclosures: Koreth: Millennium pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy. Off Label Use: Bortezomib for GVHD prophylaxis.