Abstract
Introduction: Older adults with hematologic malignancies such as AML and MDS increasingly undergo allogeneic hematopoietic cell transplantation (alloHCT). The impact of the aging host ...environment, especially cellular senescence, remains unexplored, however.
Objectives: We hypothesize that pre-transplant senescence-associated secretary phenotype (SASP) is associated with alloHCT outcomes among older patients and tested it in this biomarker correlative study.
Methods: We measured ten SASP-related cytokines (IFNγ, IL1β, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and TNFα, and C-reactive protein (CRP) from pre-transplant plasma samples of 155 patients (>50 years) who had undergone alloHCT at MSKCC from 2011 to 2019 for acute leukemias and other myeloid malignancies. Expression of aging biomarker p16 was measured on a subset of patients by immunohistochemistry.
Results and Discussion: The median age was 64.1 years (IQR 58.3 – 67.8). Diseases included 57% acute leukemias (AML and ALL) and 43% MDS/MPN. KPS was <90 in 43% and HCT-CI was >3 in 53% of patients. With median follow-up of 61 months for survivors, the 5-year OS and PFS is 50% and 46%, respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) and relapse is 18% and 31%, respectively. At the baseline, these SASP-related cytokines have variable degree of association with KPS, chronologic age, and disease risk. IL2 trended toward significant positive association with OS (HR 1.19, 95% CI 1-1.43, p=0.052) and was significantly associated with PFS (HR 1.21, 95% CI 1.02-1.44, p=0025) in univariate analysis, but not in multivariate analysis after adjusting for clinical characteristics. No cytokine was associated with NRM. IL2 and IL4 were associated with relapse in univariate but not multivariate analysis. Several cytokines including IL12 p70, IL13, IL4, and TNFα were associated with 100d grade II-IV acute GVHD in patients who received CNI-based GVHD prophylaxis. In summary, we found potential association of SASP-related cytokines with patient characteristics and transplant outcomes. We aim to validate these findings and examine their therapeutic potential to improve alloHCT outcomes.
Citation Format: Richard J Lin, Phillip Wong, Jessica R Flynn, Erika R Ritter, Caleb Ho, Josel D Ruiz, Ann A Jakubowski, Esperanza B Papadopoulos, Brian C Shaffer, Hugo R Castro-Malaspina, Christina J Cho, Doris R Ponce, Juliet N Barker, Roni Tamari, Craig S Sauter, Boglarka Gyurkocza, Marcel van den Brink, James W Young, Miguel-Angel Perales, Sean M Devlin, Sergio A Giralt. Aging-related, Senescence-associated Secretory Phenotype and Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults abstract. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A48.
•Older adults represent the fastest growing population of transplant patients.•A single-center experience of TCD transplantation in patients > 55 years is reviewed•Ex vivo TCD HSCT affords curative ...therapy with minimal GVHD in older adults.•Despite myeloablative conditioning, day +100 NRM was only 10%.
T cell–depleted (TCD) allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for hematologic malignancies in adults, shown to reduce graft-versus-host disease (GVHD) without increased relapse. We retrospectively reviewed a single-center, 11-year experience of 214 patients aged ≥ 55 years to determine tolerability and efficacy in the older adult. Most patients (70%) had myeloid diseases, and most acute leukemias were in remission. Median age was 61 years, with related and unrelated donors ≥8/10 HLA matched. Hematopoietic cell transplantation–specific comorbidity index scores were intermediate and high for 84%. Conditioning regimens were all myeloablative. Grafts were peripheral blood stem cells (97%) containing CD3 dose ≤103-4/kg body weight, without pharmacologic GVHD prophylaxis. With median follow-up of 70 months among survivors, Kaplan-Meier estimates of overall and relapse-free survival were 44% and 41%, respectively (4 years). Cumulative incidence of nonrelapse mortality at day +100 was only 10%. Incidence of GVHD for acute (grades II to IV) was 9% at day +100 and for chronic was 7% at 2 and 4 years (8 extensive, 1 overlap). Median Karnofsky performance status for patients > 2 years post-transplant was 90%. As 1 of the largest reports for patients ≥2 aged ≥55 years receiving TCD HSCTs, it demonstrates curative therapy with minimal GVHD, similar to that observed in a younger population.
Anti-PD-1 monoclonal antibodies have shown promising results in several hematologic malignancies. As a result, these agents are being tested in a growing number of clinical trials across multiple ...diseases and settings. Many participants in these trials will at some point become candidates for allogeneic hematopoietic stem cell transplant (HSCT); however, the safety and efficacy of HSCT may differ in patients previously exposed to PD-1 inhibitors given their immunomodulatory mechanism and long tissue half-life. Specifically, residual PD-1 inhibition post-HSCT could enhance allogeneic T-cell responses, which could augment the graft-vs-tumor (GVT) effect but also increase the incidence, severity or manifestations of graft-vs-host disease (GVHD) and other immune complications of HSCT.
To report our experience in this setting, we retrospectively analyzed the outcomes of patients who had received a PD-1 inhibitor prior to HSCT. Between 2013 and 2015, 19 patients who previously participated in clinical trials with either pembrolizumab or nivolumab (administered in combination with ipilimumab in 1 patient) were transplanted at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Median age at HSCT was 32 (range 22-67). Histologies included HL (n=11), DLBCL (n=2), FL (n=2), PMBCL (n=2), EATL (n=1), and MCL (n=1). Patients had received a median of 4 (2-8) lines of therapy prior to PD-1 blockade. 79% of patients had received a previous autologous stem cell transplant (21% as part of planned tandem procedure). Patients received a median of 8 (3-20) cycles of a PD-1 inhibitor; 74% had intervening salvage therapy between PD-1 blockade and HSCT, and transplant occurred a median of 130 (range 7-260) days after the last dose of PD-1 inhibitor. At HSCT, 63% of the patients were in CR and 16% had refractory disease. All patients received reduced intensity conditioning (RIC). 5 (26%) received marrow grafts from haploidentical sibling donors; the remaining 14 received peripheral blood stem cells, 5 from a matched sibling, 7 from a matched, 1 from a unidirectional host-versus-graft and 1 from a bidirectional mismatched unrelated donor. 3 cases of veno-occlusive disease (VOD) (16% of patients) were observed, one of them fatal. The 180-day cumulative incidences of grade 2-4 and grade 3-4 acute GVHD were 32% and 11%, respectively, and the 1-year cumulative incidence of chronic GVHD was 30%. There were 4 treatment-related deaths, (1 from VOD, 3 from severe acute GVHD occurring within 14 days of HSCT). In addition, 6 patients developed a febrile syndrome with elevated transaminases (n=3), rash (n= 4), and arthralgias (n=1) shortly after transplant, which required prolonged courses of steroids. Only 3 patients relapsed. After a median follow-up of 10 (3-23) months for survivors, the 1-year overall (OS) and progression-free survivals (PFS) were 78% (95CI, 52-91) and 67% (95CI, 41-84), respectively (Figure). The 1-year cumulative incidences of relapse and non-relapse mortality (NRM) were 11% (95CI, 2-30) and 22% (95CI, 6-43), respectively.
In conclusion, HSCT is feasible in patients previously treated with PD-1 inhibitors, with acceptable PFS and OS. Despite the heterogeneous patient population, small sample size, and limited follow-up to date, our results raise the possibility of important differences in the post-HSCT course of those patients. First, the relapse rate compares favorably to that expected for this cohort (1-year expected relapse rate based on Disease Risk Index mix 28%). Although this finding is at best suggestive given the sample size and follow-up time, it could reflect accentuation of GVT by prior PD-1 blockade. We also observed a high rate of severe complications including fatal early acute GVHD and VOD, with a higher NRM than expected in a RIC HSCT population. Furthermore, we noted the frequent occurrence of a steroid-responsive febrile syndrome. These possible effects of prior PD-1 blockade (including GVHD, VOD, febrile syndrome) did not appear related to the time from PD-1 treatment to HSCT, and were not reduced by intervening treatment before HSCT. As we accumulate experience with HSCT after PD-1 blockade, our early results may be relevant when considering the decision to proceed to HSCT and for the choice of transplantation strategies. We are presently expanding this analysis through a multi-center international collaborative study. Updated results will be presented at the meeting.
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Zinzani:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perales:Takeda: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Merck: Honoraria; NMDP: Membership on an entity's Board of Directors or advisory committees. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Armand:Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; BMS: Research Funding.
Background: Ex vivo T-cell depletion (TCD) by CD34+ selection has been used successfully for graft-versus-host disease prevention alleviating the need for additional pharmacologic immunosuppressants. ...TCD has been associated with higher rates of viral infections and cytomegalovirus (CMV) disease in particular compared to conventional (CONV) HCT. Modern methods of TCD achieve up to 5 log reduction of T-cells. At MSK, TCD HCT recipients (R) are routinely monitored for CMV, adenovirus (ADV), Epstein-Barr virus (EBV), and human herpes virus 6 (HHV6) in the blood by quantitative polymerase chain reaction (qPCR) assays. We report the incidence of viremia and end organ disease (EOD) by these viruses in TCD HCT recipients.
Methods: Retrospective review of adults with acute leukemia (AL) and myelodysplastic syndrome (MDS) patients (pts) who received TCD HCT at MSK from June 2010 -December 2014. TCD was performed by the FDA approved CliniMACS CD34+ reagent system (Miltenyi Biotec, Gladbach, Germany). CMV was monitored at least weekly from day 14-100 and at least every 14 days until day 180. EBV was monitored through day 180. Monitoring for CMV and EBV was performed by the Clinical Microbiology Laboratory at MSK using Roche analyte specific reagents, and since March 2013, the Cobas Ampliprep/Cobas Taqman (CAP/CTM) CMV qPCR in plasma. Monitoring for ADV/HHV6 was performed by Viracor-IBT laboratories (Lenexa, KS). Preemptive treatment for CMV was started for ≥2 consecutive PCR >500copies/ml in whole blood or >300 IU/ml in plasma. Treatment of ADV/HHV6 viremia was at clinician's discretion. EBV post-transplant lymphoproliferative disorder (PTLD) was treated with rituximab as primary therapy. During the study, 11 pts were enrolled in CMV prevention trials of brincidofovir (BCV), and 5 pts received BCV for treatment of ADV. EOD was scored by standard criteria. Follow up was through June 2015. The cumulative incidence (CI) was estimated for viremia at 180 days and EOD at 365 days for CMV, ADV, HHV6, and EBV. Kaplan-Meier method and log-rank test were used to compare CI between groups. P <0.05 was deemed statistically significant.
Results: Of239 pts (median age 56.3 years, range 19.6-73.3), 161 (67%) pts had AL and 78 (33%) pts had MDS. Donors were matched-related 76 (32%), matched unrelated 116 (48%), or mismatched (related or unrelated) 47(20%); CMV R+ 148 (62%) or R- 91 (38%). CMV infection had the earliest onset post HCT at a median of 28 days (d) (IQR: 25-33), followed by HHV6 33d (25-52), ADV 71d (44-89), and EBV 85d (58-107). 188 (79%) pts had ≥1 dsDNA viral infection with 182 (76%) pts experiencing infection prior to d100. The CIs of viremia were: CMV 42% (68% in R+ vs 0% in R-, P <0.0001), ADV 7% (10% in R+ vs 5% in R-, P =0.02), EBV 19%, and HHV6 61%. The CI of EBV and HHV6 viremia were similar between R+ and R- (P =NS). Among 100 pts with CMV viremia, 62 (62%) had dsDNA viral coinfections; including 40 (40%) with 1 coinfection, 19 (19%) with 2 coinfections, and 3 (3%) with 3 coinfections. Antiviral treatment was given to 99 pts for CMV (99% of CMV viremic pts, 67% of R+, 41% of total pts), 9pts for ADV (56% of ADV viremic pts; 4% of total), and 19 for HHV6 (16% of HHV6 viremic pts; 8% of total). In total, 42 (18%) pts developed EOD by dsDNA viruses. The most common EOD was EBV PTLD (20 pts, 9%), followed by CMV (14 pts, 7%; but 11% among CMV R+ pts), ADV (8 pts, 4%), and HHV6 (2 pts, 1%). Among 14 pts with CMV disease, 6 had pneumonitis, 5 colitis, 3 duodenitis, and 3 retinitis. Three pts had 2 sites of CMV EOD. Among 8 pts with ADV disease, 3 had colitis, 3 pneumonitis, 1 nephritis, and 1 hepatitis/colitis. Two pts had HHV6 pneumonitis.
Conclusions: 1) Viremias by dsDNA viruses occurred frequently and early post TCD HCT: 189 (79%) pts had at least 1 dsDNA viral infection, with onset of first infection before d100 in 183 (77%) pts. Around 58% of pts with CMV had coinfections with additional dsDNA virus(es). 2) Two thirds (67%) of CMV R+ and 41% of total pts received CMV antiviral treatment. 3) Overall, 18% of patients developed end organ disease by dsDNA viruses. 4) Viremias were managed effectively with intense monitoring and antiviral treatment, and rates of EOD were comparable to those of CONV HCT. Our data highlights the need for effective strategies to reduce the total burden of dsDNA viruses after TCD HCT.
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Perales:Merck: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.
Background: Peripheral T-cell lymphomas (PTCL) are an uncommon heterogenous subset of non-Hodgkin lymphomas for which allogeneic hematopoietic stem cell transplantation (HSCT) is often recommended in ...the relapsed/refractory setting.
Methods: We analyzed overall (OS) and progression-free survival (PFS) in all adults with PTCL who were transplanted 3/2001-12/2014.
Results: Patient characteristics are shown in the Table. 65 patients (pts) identified (median age 50.3 years, range 18-70) had a median number of prior treatment regimens of 3 (range 1-8), 42 (65%) were in complete remission (CR) at HSCT (24 in 1st and 18 in > 1st) and 15 in partial remission (PR), 10 (15%) pts had a prior autologous transplant, and the median hematopoietic cell transplant comorbidity index (HCT-CI) score was 2 (range 0-8). Conditioning was myeloablative (MA) in 23, reduced intensity (RIC) in 22, and non-myeloablative (NMA) in 20 pts. Grafts were matched sibling (n=33), mismatched sibling (n=1) matched unrelated donor (MUD) (n=16), mismatched unrelated donor (n=7) or cord blood (n=8). The median day to neutrophil engraftment was 12 (range 9-29), 12 (range 11-23), and 10 (range 8-21) for MA, RIC and NMA respectively. Seventeen (26%) pts had grade II-IV day +100 acute graft-versus-host disease (GvHD) (7 grade II, 7 grade III, 3 grade IV). Eighteen pts (28%) had chronic GvHD. Twenty-one pts have relapsed to date at a median of 3.25 months (range 1.81-71.79). With a median follow-up period for survivors of 41.7 months (range, 6.4-163 months), the OS and PFS rate were 59% and 48% at 2 years (Figure 1). All deaths occurred within 36 months of HSCT. Of 27 pts who have died, 14 died of lymphoma and 13died of HSCT complications. The rate of transplant related mortality (TRM) at 1 year was 17% (95%CI: 7.7-26.1). Causes of death included graft failure (n=1), GvHD (n=7), infection (n=1), pulmonary complications (n=2), cardiac arrhythmia (n=1) and veno-occlusive disease (n=1). There were no differences in TRM according to recipient age, HCT-CI, Karnofsky performance status (KPS), number of prior regimens, prior radiation, receipt of a prior autologous transplant, disease status prior to HSCT or conditioning intensity (all p-values NS). PFS was not affected by disease status prior to HSCT. Degree of HLA-match was significantly associated with TRM (p<0.0001). For pts who underwent matched unrelated, matched related or mismatched donor HSCT, cumulative mortality at 6 months was 6%, 9% and 44%, respectively (Figure 2). Seven of 21 pts who relapsed survive to date, median of 63 months post relapse (range 12-153 months) after treatment with chemotherapy only (n = 2), donor lymphocyte infusion (DLI) (n=3), DLI + HSCT (n=1) or a 2nd HSCT (n=1).
Conclusions: We present the largest single center series of HSCT in PTCL. This study suggests existence of GvL effects in patients with PTCL regardless of conditioning intensity or depth of remission at HSCT. Mismatched HSCTs were associated with higher TRM; mainly GvHD. Events were not seen beyond 36 months. This data supports the curative potential of HSCT in a patient group with otherwise poor survival.
TablePatient CharacteristicsDiseaseType(N)Median(range)AgeMedian(range)HCT-CIRemissionStatusMedian (range) Prior Regimens/N prior autoRegimenIntensity2-yr PFS(95%CI)PTCL NOS (n=15)52 (30-67)3 (0-7)12 CR 3 PR3 (1-6) 17 MA 4 NMA 4 RIC45% (20%-68%)AITL (n=11)52 (30-70)1 (0-8)8 CR 3 PR3 (1-5) 52 MA 4 NMA 5 RIC81% (44%-95%)ALCL (n=5)47 (28-69)1 (0-5)4 CR 1 PR3 (2-8) 22 MA 2 NMA 1 RIC2 DF 24 & 89 mo; 3 TRM by 15 moCTCL (n=10)/ SPTCL (n=4)47.2 (21-61)1 (0-5)6 CR 8 PR3 (2-8) 03 MA 5 NMA 6 RIC43% (17%-66%)ATLL (n=8)50 (34-68)1.5 (0-6)5 CR 3 PR1 (1-6) 02 MA 3 NMA 3 RIC37% (8%-67%)HSTCL (n=7)28 (18-64)1 (0-4)4 CR 2 PR 1 S1 (1-4) 14 MA 1 NMA 2 RIC38% (6%-71%)NK (n=3)42 (24-47)0 (0-1)2 CR 1 PR1 (1-2) 03 MA1 DF 59 mo 1 TRM 1 DiseaseTPLL (n=1)564CR1/0RIC1 DiseaseEATL (n=1)525CR3/1NMADF 24 moPTCL- peripheral T cell lymphoma (TCL); AITL- angioimmunoblastic TCL,; ALCL- anaplastic large cell lymphoma; CTCL- cutaneous TCL; ATLL- adult TCL; SPTCL- subcutaneous panniculitis TCL; HSTCL- hepatosplenic gamma delta TCL; NK- natural killer TCL; TPLL-prolymphocytic TCL; EATL- enteropathy TCL; CR - complete remission; PR - partial remission; S - stable disease; MA- myeloablative; RI- reduced intensity; NMA- non-myeloablative; mo- month; DF Disease-free
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Perales:NMDP: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Merck: Honoraria; Takeda: Honoraria.
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The major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are relapse, graft-versus-host disease (GVHD), and infection. We have previously reported that ...changes in the intestinal flora can affect GVHD, bacteremia, and overall survival. As intestinal bacteria are potent modulators of systemic immune responses, and since GVHD is correlated with graft-versus-tumor activity, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HSCT.
We applied a biomarker-discovery approach and performed a retrospective observational analysis of 160 adults who received an unmodified (T-cell-replete) allograft. Patients were prospectively enrolled in a fecal biospecimen-collection protocol. For this analysis, we selected patients who had at least one specimen during the first 3 weeks following allo-HSCT. The primary diseases in this cohort were AML (37%), Non-Hodgkin's Lymphoma (33%), ALL (8%), MDS (7%), CLL (6%), Hodgkin's Lymphoma (6%), CML (2%), and myeloproliferative neoplasm (2%). The mean age of the patients was 52 years (range 21-75). They were conditioned with ablative (17%), reduced-intensity (64%), and nonmyeloablative (19%) regimens. They received grafts from cord blood (46%), unrelated adults (33%), or related adults (22%). Among adult grafts, 92% were from peripheral blood and 8% were from bone marrow.
A census of the bacterial species in each stool sample was generated by 16S rRNA deep-sequencing as previously described (Jenq et al., BiolBone Marrow Transplant 2015). The area under the curve of bacterial abundance over time was used as a measure of each patient's cumulative exposure to each bacterial taxon. Bacterial taxa of each patient present at a frequency >1% were evaluated for association with the outcome of relapse or progression of disease within the first year after allo-HSCT using linear discriminant analysis of effect size (LEfSe), a common approach in microbiota studies (Segata et al., Genome Biology, 2011).
Among the taxons most significantly associated with freedom from relapse were members of the human oral flora including Streptococcus anginosus. After stratifying the patients by median abundance, we found that those with higher abundance of this bacterium had less relapse after transplantation (Left figure, p = 0.0014). We also identified bacteria associated with increased risk of relapse, such as Enterococcus faecium (Right figure, p = 0.0103).
We evaluated these bacteria as biomarkers in multivariate Cox models adjusted for three factors that were associated with relapse in this cohort: Refined Disease Risk Index (RDRI, Armand et al., Blood 2014), conditioning intensity, and graft source (cord blood vs. adult donor). Streptococcus anginosus predicted relapse in a multivariate model adjusted for all three factors (HR 0.39, 95% CI 0.16-0.96, p = 0.041). Enterococcus faecium predicted relapse in a model adjusted for RDRI and conditioning intensity but failed to do so in a model additionally adjusted for graft source. In this analysis there was no formal adjustment for multiple comparisons; these data are now being validated in an additional cohort of patients whose samples are being sequenced. Finally, although we have previously reported that low bacterial diversity is associated with decreased overall survival after allo-HSCT (Taur et al., Blood 2014), we did not find an association between bacterial diversity and relapse as assessed by reciprocal Simpson diversity index (p > 0.1).
Thus, the results of this retrospective analysis have identified an association between relapse after allo-HSCT and the abundance of two bacteria in the intestinal flora. These might serve as potential novel diagnostics or therapeutic targets to prevent relapse and improve overall survival after allo-HSCT.
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Peled:Merck: Research Funding. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Research Funding. Perales:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Astellas: Honoraria; NMDP: Membership on an entity's Board of Directors or advisory committees. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee; Regeneron: Honoraria; Merck: Honoraria.
Introduction: Systemic evaluation of toxicities after allogeneic hematopoietic stem cell transplantation (allo-HCT) has been limited. Ex vivo CD 34+ selection prior to allo-HCT reduces GVHD without ...increasing relapse, but is usually done in the context of myeloablative conditioning. Comprehensive collection of toxicities is particularly important in older patients (pts) who usually receive a reduced intensity conditioning.
Aim: To identify toxicity patterns in older pts and their association with overall survival (OS) and non-relapse mortality (NRM).
Methods: A retrospective analysis was performed at Memorial Sloan Kettering Cancer Center (MSKCC) including 200 pts who underwent CD34+ selection allo-HCT using the ClinicMACS® system between 2006-2012. All grade 3-5 toxicities by CTCAE v4.0 were collected and compared between pts ≥ 60 or <60yrs. Individual toxicities were organized into 91 toxicity categories and further into 17 organ-based groups. One toxicity per group per specified time period was used for statistical analyses. OS and NRM were calculated using Kaplan Meier methodology, and Cox regression was used for univariate analysis of risk of toxicities and survival outcomes across patient and treatment characteristics.
Results:
Eighty pts ≥ 60yrs with a median age of 64 (range 60-73) were compared to 120 pts <60yrs (Table 1). Busulfan, fludarabine, and melphalan conditioning with rabbit ATG was used in 72% of pts. Pts <60 were more likely to receive total body irradiation (45 vs 3%, p<0.001). Median follow-up in survivors was 48.2 months.
OS was not different between ≥60 and <60, with a 1-yr OS 70% vs 78% (p=0.07), respectively. NRM at 1-yr was also similar, 23% vs 13% (p=0.38), respectively (Figure 1A).
In pts ≥60, the most common toxicities by day 100 were metabolic with a cumulative incidence of 88% (95% CI 78-93%), infectious 84% (73-90%), hematologic 80% (69-87%), oral/gastrointestinal (GI) 48% (36-58%), cardiovascular (CV) 35% (25-46%), and hepatic 25% (16-35%). Pts ≥60 had a higher risk of neurologic HR 2.63 (1.45 to 4.78), p=0.001 and CV HR 1.65 (1.04 to 2.63), p=0.03 toxicities, but lower risk of oral/GI HR 0.58 (0.41 to 0.83), p=0.003 compared to <60.
Univariate analysis of baseline characteristics identified associations with the most common toxicities in the first year. In pts ≥60, metabolic toxicity was increased if the donor was CMV seropositive HR 1.9 (1.2-3.1), p=0.01, and decreased with albumin ≥ 4 HR 0.6 (0.4-0.9), p=0.02 and an unrelated donor HR 0.5 (0.3-0.9), p=0.01. Diagnosis of multiple myeloma (MM) was associated with increased hematologic toxicity HR 3.04 (1.4-6.4), p<0.001. Risk of oral/GI toxicity was increased with patient CMV seropositivity HR 2 (1.1-3.9), p=0.03 and decreased in males HR 0.5 (0.3-0.9), p=0.02. Both ferritin >1000 HR 3.5 (1.5-7.9), p=0.002) and patient CMV seropositivity HR 2.8 (1.3-6.3), p=0.01 increased the risk of hepatic complications. No baseline characteristics were significantly associated with infectious or cardiovascular toxicities.
The median number of toxicities at Day 100 was 6. OS was not significantly different in pts ≥60 with ≥ median toxicities compared to pts with < median toxicities, and when compared to pts <60 yrs (p=0.65) (Figure 1B).
In further univariate analysis in pts ≥ 60 including baseline characteristics and the 17 toxicity groups, diagnosis of MM was the only baseline characteristic associated with worse OS (HR 2.4, p=0.04). NRM was increased with each year post age >60 (HR 1.2, p=0.004), the need to adjust busulfan dose lower (HR 3.1, p=0.03), patient CMV seropositivity (HR 2.7, p=0.04), and an HCT-CI ≥3 (HR 5.19, p=0.016). CV, endocrine, hepatic, neurologic, pulmonary, and renal toxicities were associated with worse OS, while CV, hepatic, neurologic, pulmonary, renal, and skin toxicities increased the risk of NRM (Table 2).
Conclusions: Older pts had similar OS and NRM when compared to younger pts, and the toxicity of a more intense regimen is potentially balanced by the absence of toxicity related to methotrexate and calcineurin inhibitors. While the median number of toxicities was similar between younger and older pts and to unmanipulated grafts based on reports of the BMT CTN, there was a difference in the type of toxicities by age. This is the first comprehensive toxicities assessment post CD34+ selected allo-HCT, and a prospective exploration of CD34+ selection in older pts is essential.
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Koehne:Atara Biotherapeutics: Consultancy. Perales:Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO ...2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT.
METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis.
RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p < 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI.
In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score > 0, KPS < 90, donor type (matched unrelated or mismatched vs. matched related donor), and age > the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, 95% CI 1.24, 2.40) and relapse or death (HR 1.86 for RFS 95% CI 1.35, 2.55), compared with low/intermediate DRI. Multivariate analysis also showed that KPS < 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis.
CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301).
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Koehne:Atara Biotherapeutics: Consultancy.
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Introduction: Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The portion of patients referred for transplant and ...the proportion who are subsequently transplanted is unknown.
Aim: Tostudy the frequency of allo-HCT in pts with MDS and identify factors associated with transplant referral and barriers to transplant.
Methods: Pts were included if they were under the age of 75 and seen at our center by a leukemia physician between 2008-2015 and within 6 months of MDS diagnosis. Pts were eligible for allo-HCT if they did not have major organ dysfunction, i.e. left ventricular ejection fraction <40%, Creatinine >2mg/dL, FEV1 <1L, DLCO <50%, metastatic solid organ malignancy within 5 years of MDS diagnosis and had KPS <60. Allo-HCT was indicated in pts with therapy related MDS (tMDS), MDS with excess blasts (RAEB-1 or 2), IPSS int-2 or High risk and in cases of life threatening cytopenia (ANC <0.5x109/L, Plt<30x109/L, Hb <7gm/dL). Pts not meeting any of these criteria at diagnosis but who developed >5% marrow blasts during follow-up were eligible for allo-HCT from date of disease progression.
Results: This was a single center study.362 pts were identified with a median follow-up of 14 months. 294 (81.2%) were eligible for allo-HCT and in this group transplant was indicatedin 244 (83%). Of these 158 (65%) were referred for transplant evaluation and 109 (69%) of those underwent allo-HCT (figure 1).
Reasons for transplant ineligibility at diagnosis and reasons for eligible patients not undergoing transplant are listed in table 1. Metastatic solid organ malignancy within 5 years of MDS diagnosis accounted for most cases of transplant ineligibility (54%), and death due to MDS and progression of disease at last follow-up (60%) were the major reasons for eligible patients not undergoing transplant. Lack of a suitable donor was rarely the primary reason for not proceeding with transplant (3%).
Factors associated with a lower likelihood of referral for transplant evaluation were primarily patient related including age over 65 (p=0.001), presence of 3 or more co-morbidities (p=0.003) and RAEB-1 or 2 (p=0.009) at diagnosis. Earlier referral was associated with high-risk disease including tMDS (p=0.006); excess blasts (p=0.001); high-risk IPSS (p=0.001) or IPSS-R (p=0.001) while patient factors including age (p=0.421), gender (p=0.258), KPS (p=0.143) and number of comorbidities (p=0.247) were not associated with time to referral. Pts diagnosis between 2014 and 2015 were referred earlier then in prior years (p<0.001).
Among eligible pts in whom transplant was indicated, patient factorswere associated with a higher likelihood of undergoing transplant (table 2) including younger age, female gender, KPS over 90 and having fewer co-morbidities. Specific comorbidities associated with a reduced likelihood of undergoing transplant included coronary or cerebrovascular disease or diabetes. MDS disease features including IPSS (p=0.390), blast percentage at diagnosis (p=0.061), progression to RAEB (p=0.992) or AML (p=0.776) and earlier referral for transplant evaluation (p=0.068) were not associated with a greater likelihood of undergoing transplant. 11 pts were transplanted despite not meeting our transplant indications. These pts had a longer median time to transplant from the time of BMT assessment and underwent allo-HCT most likely due to progressive cytopenia (Figure 1)
Conclusion: Allo-HCT is underutilized in MDS patients with only 64% of eligible patients referred for evaluation and 69% of those referred undergoing transplant. Death due to MDS and disease progression were the major barriers to transplantation. The decision to refer a patient for transplant evaluation was influenced by the physician's assessment of the patient's functional eligibility (age, KPS, number of comorbidities) while the urgency of referral was influenced by disease risk. Development of reduced toxicity conditioning protocols, improved GVHD prophylaxis, extended donor options and optimization of supportive care mean older pts with higher co-morbidity scores should be referred for transplant assessment and those with low risk disease should be referred early so that donor options can be identified and a plan for transplant can be prepared prior to disease progression.
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No relevant conflicts of interest to declare.
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