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 × 106 IU/m2) 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 rose >fivefold (P < .001) and >fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rose >fivefold (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.
•Low-dose IL-2 is efficacious in steroid-refractory cGVHD, with objective responses in >50% of patients, and durable disease control.•IL-2 initiation earlier after cGVHD onset, prior to severe impairment of Treg:Tcon ratios, improves likelihood of clinical response.
Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline
mutation carriers (
carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among
...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
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.
carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m
every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m
; cyclophosphamide 600 mg/m
every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review.
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
+, 30% were
+, 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.
pCR or RCB 0/1 is not significantly higher with CDDP than with AC in
carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
Summary
Inhibition of the mechanistic target of rapamycin (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‐IV acute GVHD (9% vs. 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).
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-
-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-
-host disease between conventional tacrolimus/methotrexate (A)
bortezomib/tacrolimus/methotrexate (B), and
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-
-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-
-host disease rates were similar (A 32.6%, B 31.1%, C 21%;
=0.53 for A
B,
=0.16 for A
C). The 2-year non-relapse mortality incidence was similar (A 14%, B 16%, C 6.4%;
=0.62), as were relapse (A 32%, B 32%, C 38%;
=0.74), chronic graft-
-host disease (A 59%, B 60% C 55%;
=0.66), progression-free survival (A 54%, B 52%, C 55%;
=0.95), and overall survival (A 61%, B 62%, C 62%;
=0.98). Overall, the bortezomib-based regimens evaluated did not improve outcomes compared with tacrolimus/methotrexate therapy.
.
Abstract
Background
The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased ...risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints.
Methods
We examined serial samples from 40 older women with triple-negative or hormone receptor–positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks).
Results
CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02).
Conclusions
Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies.
Trial Registration
ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.
Older adults with breast cancer receiving neo/adjuvant chemotherapy are at high risk for poor outcomes and are underrepresented in clinical trials. The ADVANCE (ADjuVANt Chemotherapy in the Elderly) ...trial evaluated the feasibility of two neo/adjuvant chemotherapy regimens in parallel-enrolling cohorts of older patients with human epidermal growth factor receptor 2-negative breast cancer: cohort 1—triple-negative; cohort 2—hormone receptor-positive.
Adults age ≥ 70 years with stage I-III breast cancer warranting neo/adjuvant chemotherapy were enrolled. Cohort 1 received weekly carboplatin (area under the curve 2) and weekly paclitaxel 80 mg/m2 for twelve weeks; cohort 2 received weekly paclitaxel 80 mg/m2 plus every-three-weekly cyclophosphamide 600 mg/m2 over twelve weeks. The primary study endpoint was feasibility, defined as ≥80% of patients receiving ≥80% of intended weeks/doses of therapy. All dose modifications were applied per clinician discretion.
Forty women (n = 20 per cohort) were enrolled from March 25, 2019 through August 3, 2020 from three centers; 45% and 35% of patients in cohorts 1 and 2 were age > 75, respectively. Neither cohort achieved targeted thresholds for feasibility. In cohort 1, eight (40.0%) met feasibility (95% confidence interval CI = 19.1–63.9%), while ten (50.0%) met feasibility in cohort 2 (95% CI = 27.2–72.8). Neutropenia was the most common grade 3–4 toxicity (cohort 1—65%, cohort 2—55%). In cohort 1, 80% and 85% required ≥1 dose holds of carboplatin and/or paclitaxel, respectively. In cohort 2, 10% required dose hold(s) for cyclophosphamide and/or 65% for paclitaxel.
In this pragmatic pilot examining chemotherapy regimens in older adults with breast cancer, neither regimen met target goals for feasibility. Developing efficacious and tolerable regimens for older patients with breast cancer who need chemotherapy remains an important goal.
ClinicalTrials.gov Identifier: NCT03858322.
•The E. coli lacZ reversion assay was used to measure mutation frequencies.•Revertant frequencies are higher when there are fewer viable cells per plate.•The increase in revertant frequency shares ...properties with adaptive mutation.•An artifact that mimics mutagenesis may occur after toxic but nonmutagenic treatments.
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.
Abstract
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 <10%). Histologic type and grade, clinical stage, lymphovascular invasion and tumor infiltrating lymphocytes were similar between treatment arms. Four patients did not complete protocol-assigned therapy and 7 received additional chemotherapy before surgery; all were assessed as not attaining pCR. The pCR rate was 18% in the CDDP arm and 26% in the AC arm, yielding a crude risk ratio of 0.70 (95% CI: 0.35-1.4); results were similar when adjusting for ER status. Table 1 shows pathologic responses.
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 <10%)10 (23)11 (29)0.79 (0.37-1.6)–Hormone receptor positive (ER or PR ≥10%)1 (6)4 (21)0.30 (0.04-2.4)–Residual cancer burden¥Residual cancer burden score: 0 or 120 (33)26 (46)0.73 (0.46-1.2)0.72 (0.46-1.1)*One patient never received treatment, and is not included in the intent-to-treat analysis.§Adjusted for estrogen receptor status using 10% cutoff¥Residual cancer burden score of 0 or 1 could not be determined for 10 participants; they were assumed to have a residual cancer burden score greater than 1
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.
Abstract 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 .)
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.
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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.
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