Abstract Keratoconjunctivitis sicca (KCS) occurs in 40%-60% of patients with chronic graft-versus-host-disease (cGVHD) after allogeneic hematopoietic cell transplantation. Although immunosuppressive ...therapy is the primary treatment of chronic GVHD, ocular symptoms require measures to improve ocular lubrication, decrease inflammation, and maintain mucosal integrity. The liquid corneal bandage provided by a fluid-ventilated, gas-permeable scleral lens (SL) has been effective in mitigating symptoms and resurfacing corneal erosions in patients with KCS related to causes other than cGVHD. We report outcomes in 9 consecutive patients referred for SL fitting for cGVHD-related severe KCS that was refractory to standard treatments. All patients reported improvement of ocular symptoms and reduced the use of topical lubricants after SL fitting resulting from decreased evaporation. No serious adverse events or infections attributable to the SL occurred. The median Ocular Surface Disease Index improved from 81 (75-100) to 21 (6-52) within 2 weeks after SL fitting, and was 12 (2-53) at the time of last contact, 1-23 months (median, 8.0) after SL fitting. Disability related to KCS resolved in 7 patients after SL fitting. The use of SL appears to be safe and effective in patients with severe cGVHD-related KCS refractory to conventional therapies.
A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, ...mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.
Haploidentical hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with promising ...results. However, limited data are available on the incidence, pattern, and risk factors including donor/recipient KIR genotypes for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes is not yet well-described. In this retrospective study, we evaluated a series of 119 consecutive patients who underwent HaploHCT with PTCy at City of Hope for hematological diseases, between January 2009 and December 2016. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500 gc/ml, qualitative limit: 250 gc/ml) at least once a week for 100 days post-transplant, with preemptive anti-CMV therapy for positive PCR according to our institutional guidelines.
The median age of the cohort was 43 years (range: 2 to 71 years); with 47 female and 72 male patients. CMV serostatus of donor/recipient was Donor−/Recipient− (D−/R−) in 7, D+/R− in 6, D−/R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling haploidentical donors (n=77). Graft-versus-host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2), and the HCT-comorbidity index was more than 2 in 42% (n=50) of patients.
Cumulative incidence (CI) of CMV reactivation for the entire cohort was 68.1% (95%CI: 58.8-75.7%) at 100-days, with the median time to reactivation at 35 days (95%CI: 33-40); 76.2% in seropositive recipients and 7.7% in seronegative recipients (p<0.001). (Figure 1) Among 81 patients with any CMV reactivation; median initial viral load was 624 copies/mL (range: <500- 9930) and peak viral load was 2601 copies/mL (range: <500-166,865) with median CMV area under the curve (AUC) of 28,002 (range: 1671.0-2,149,929.5). In seropositive recipients (n=105), CI of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset of CMV reactivation at 33 days (95%CI: 30-36). Majority of patients (n=62) experienced only one reactivation episode with the median duration of 17 days (range=1-62) while 16 patients experienced more than one reactivation episodes with the median duration of 63.5 days (range: 33-78). Prolonged CMV exposure (>17days of CMV viremia) was seen in 47 patients.
In univariate analysis; recipient CMV serostatus, recipient sex, and stem cell source were statistical significant factors, affecting CI of CMV reactivation, but only recipient CMV serostatus stood as an independent factor on multivariable analysis (HR=15.5, 95%CI: 2.3-106.3 for R+ compared to R−, p=0.005) (Figure 1). We also evaluated the effect of KIR status on the CI of CMV reactivation. Multivariable analysis indicated a trend towards decreased incidence of CMV reactivation in donors with 2DS5 and 3DS1 (HR= 0.71 for both donors; p value= 0.1). Donor-recipient KIR mismatch was also associated with a trend towards increased incidence of CMV reactivation (p=0.1) and statistically significant prolonged CMV reactivation (OR=2.48, 95%CI: 1.12-5.47, p=.025).
With median follow up duration of 24.3 months (range: 10.3 to 99.2) and in univariate analysis, CMV reactivation, higher peak CMV PCR, time to CMV reactivation, or prolonged exposure to CMV were not associated with worse overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Interestingly, the risk of extensive chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (41.9% vs. 26.2%, p= 0.046)
In conclusion, recipient and not donor serostatus is predictive of CMV reactivation in HaploHCT with PTCy. With the current pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease or worse survival outcome. Donor-recipient KIR match (KIR licensing) and donor activating KIR genes (2DS5 and 3DS1) may be involved with CMV control after HaploHCT.
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Dadwal:MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding; AiCuris: Research Funding; Gilead: Research Funding. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.
To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus ...leukemia effect observed in allogeneic transplantation.
Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10(6) U/m(2)/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10(6) U/m(2)/24 h on hematologic recovery.
Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval CI, 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate.
These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin-mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.
Haploidentical donor hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with ...promising results. However, limited data is available on the incidence, pattern, and risk factors for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes has not been well understood in these patients. In this retrospective study we evaluated 119 consecutive patients undergoing HaploHCT for hematological diseases using PTCy between January 2008 and December 2016 at City of Hope under the IRB approved protocol. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500gc/ml, qualitative limit: 250gc/ml) at least once a week for 100 days post-HCT, with preemptive anti-CMV therapy for positive PCR according to the institutional guidelines.
The median age of the cohort was 43 years (range: 2 to 71 years); 47 patients were female and 72 were male. CMV serostatus of donor/recipient was D-R- in 7, D+R- in 6, D-R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced-intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling Haplo donor (n=77). Graft versus host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2). The HCT-comorbidity index was more than 2 in 42% (n=50) of the patients.
Cumulative incidence (CI) of CMV reactivation for the entire cohort was 69.2% (95%CI: 59.8-76.8%) at 100-days, with the median time to reactivation at 35 days (Figure 1a). While for seropositive recipients (n=105), cumulative incidence of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset at 33 days. The median CMV PCR values at onset was 624 gc/ml (range: <500 - 9,930) while the median peak PCR value during the 100-day period was 2965 gc/ml (range: <500 - 221,125). The median duration of CMV reactivation was 21 days and 28% (n=33) of patients had recurrent CMV reactivation during the first 100 days post-HCT. In our cohort there was no patient who developed CMV disease.
In univariate analyses the only significant risk factor for CMV reactivation was recipient serostatus (HR=0.06, 95%CI: 0.01 to 0.40 for R- compared to R+, p<0.001) (Figure 1b). Acute GVHD (aGVHD) was not associated with CMV reactivation when analyzed as a time-dependent variable partly due to lower incidence and later onset of aGVHD (100 days incidence: 36.7%; median onset day was not reached, range= 18 to 88) than CMV reactivations (median: 33 days, range= 7 to 54).
We then evaluated the impact of CMV reactivation in a landmark analysis of 101 patients who were relapse free for 100 days. The median follow up duration in this subgroup was 12.3 months (range: 3.4 to 99.1). In univariate analysis, CMV reactivation was not associated with overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Similarly, the high-peak CMV reactivation or prolonged CMV reactivation (total duration or total episodes) was not predictive of poor outcomes in this cohort. Interestingly, the risk of chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (56.0% vs. 20.5%, p= 0.048, Figure 2).
In conclusion, HaploHCT with PTCy was associated with a high rate of CMV reactivations in seropositive recipients. However, due to pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease. Despite many patients requiring a long course of preemptive anti-CMV therapy, there was no obvious association between CMV reactivation and survival outcomes. The observed association between CMV reactivation and reduced risk of chronic GVHD warrant further clinical and correlative immunologic studies.
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Nademanee:seattle Genetics: Speakers Bureau.
Background:
Chronic graft-versus-host disease (cGVHD) remains a common and potentially life-threatening complication after allogenic hematopoietic stem cell transplantation (HCT). Systemic ...corticosteroids are first-line therapy, however, they are often associated with inadequate responses and multiple side effects. There has been no single standard therapy for refractory cGVHD. Recently, ruxolitinib, a selective JAK1/2 inhibitor, has been suggested to have efficacy as salvage therapy in cGVHD. However, data are limited to a multi-center retrospective survey of 41 patients (Zeiser et al. Leukemia. 2015; 29(10):2062-8). Herein, we present a single-institution's experience with ruxolitinib as salvage therapy for management of refractory cGVHD.
Methods:
In this single-center, IRB-approved, retrospective analysis, the charts of 47 patients who received ruxolitinib as salvage therapy for cGVHD from March 2016 through December 2016 were reviewed. Clinical data were collected and analyzed at start of ruxolitinib treatment, 3 months-post, and 6 months-post to identify changes in prednisone dose, patient perceived improvement, physician perceived improvement, and incidence of adverse events including hospitalizations, documented infections, cytopenias, relapse, and death. In addition, we assessed for treatment failure-free survival (FFS) from the time of ruxolitinib to any of the following events: initiation of new cGVHD therapy, relapsed disease, patient death, or discontinuation of ruxolitinib.
Results:
The cohort consisted of 47 patients (median age = 51; range = 21 - 91; 21 females and 26 males) who received fully ablative (n=26) or reduced-intensity conditioning (n=18) followed by an allogeneic HCT from matched related donor (n=15), unrelated donor (n=13), or other donor sources (cord or haplo-identical donors: n=16) for their hematologic disorders. The median time from HCT to ruxolitinib initiation was 40.5 months (range: 3.8 to 267.2). Of the 47 patients in this cohort, 38 patients (80.9%) had sclerotic chronic graft versus host disease.
The average dose of prednisone in evaluable patients was 11.1 mg/day (95% CI 6.9 - 15.3 mg/day) at time of ruxolitinib initiation, which decreased to 7.7 mg/day (95% CI 4.1 - 11.4 mg/day, p=0.043 by paired signed rank test, 30% reduction) at 3 months, and 5.6 mg/day (95% CI 3.2 - 8.0, p<0.001, 49% reduction) after 6 months of ruxolitinib therapy. There were 12 patients (36%) and 14 patients (42%) who experienced prednisone dose reduction at 3 & 6 months, respectively. Patient-reported subjective improvement was observed in 22 of 41 evaluable patients (53.7%) and 23 of 37 evaluable patients (62.2%) at 3 and 6 months, respectively. Physicians rated subjective improvement in 29 patients (70.7%) at 3 months and 25 patients (67.6%) at 6 months. Infections were documented in 25 patients (56.8%), of which 6 (12.8%) were considered life-threatening. Two patients (4.2%) with CMV viremia with no end-organ disease were identified. Significant cytopenias requiring ruxolitinib dose reduction or discontinuation were observed in 3 patients (7.0%). During the study period of 6 months, 18 patients (40.9%) required hospitalization at least once, and 6 patients (12.8%) died within first 6 months of ruxolitinib use. Treatment failure-free survival at 6 months was 68.1% (95%CI; 52.7% to 79.4%) with the failure events including death (n=6), relapse (n=2), addition of new therapy (n=2), and discontinuation of ruxolitinib for any reason other than resolution of cGVHD symptoms (n=6) (Figure 1).
Conclusion:
Ruxolitinib is associated with prednisone reduction after 3 and 6 months, self-/physician-reported improvements, and favorable FFS at 6 months in patients with steroid-refractory chronic GVHD. Prospective randomized trials are warranted to further define its therapeutic benefits and risks of cytopenia/infectious complications.
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Salhotra:Kadmon: Consultancy.
Allogeneic hematopoietic stem cell transplant (alloHCT) remains the only potentially curative treatment for patients with myelodysplastic syndrome (MDS). However, this treatment is associated with ...significant risk of transplant-related mortality/morbidity such as graft-versus-host disease, infections, and regimen-related toxicities. Since there has been no “randomized” trial comparing between patients undergoing or not undergoing transplantation, the relative benefit of this treatment, particularly in elderly patients, is largely unknown. Retrospective comparative studies are significantly limited by the inherent selection bias of healthier/well-supported patients in the alloHCT group. Therefore, a critical knowledge gap exists regarding the survival outcome of MDS patients who are transplant eligible yet did not undergo alloHCT due to lack of suitable donors or other reasons.
Herein, we retrospectively identified a consecutive case-series of 73 patients with MDS (excluding CMML), who were considered alloHCT candidates, based on initiation of an official donor search from 2005 to 2015, yet did not proceed with alloHCT. Median age at time of donor search was 60 years (range: 20-79) with the majority (63%) being male. Classifications of MDS were single or multi-lineage dysplasia (n=20), excess blast (n=39), MDS unclassified (n=6) or other/unknown classification (n=8). The cohort included 51 de novo MDS and 14 therapy-related MDS (t-MDS). Per International Prognostic Scoring System (IPSS) 29 patients (39.7%) were Intermediate (Int)-1, 14 (19.2%) were Int-2, and 23 (31.5%) were high risk at the time of donor search (Table 1). Reasons for no alloHCT were lack of donor (n=29), persistent/progressive disease (n=9), patient choice (n=13), or infections/complications after initiating the donor search (n=18). Treatments of these patients included chemotherapy (n=14), hypomethylating agents (n=61) and supportive care (n=23). Of the 73 patients, 15 (20.5%) had disease progression to acute leukemia at 1 year. There were 38 deaths with the median OS of 26.2 months (95%CI: 17.3-48.3 months). The 2-year probability of OS was 51% (95%CI: 36.7-62.9%).
We next compared outcomes of these MDS patients who had a donor search without subsequent HCT to a consecutive case-series of MDS patients who underwent alloHCT from matched related and unrelated donors (cord blood and haploidentical transplants were excluded) during the same time period (n=276) at our center (Aldoss et al. Haematologica 2017). Patient demographics and MDS disease characteristics were similar between the two groups (Table 1). Median number of days from HLA typing to HCT were 168. By Kaplan-Meier method, OS (from the time of donor search) was significantly better for the alloHCT group (74% at 2-years) compared with non-HCT group (51% at 2-years), log-rank P<0.001 (Figure 1a). This survival benefit was primarily driven by the subgroup of patients with int-2/high risk IPSS. While the difference in the OS did not reach statistical significance in low/int-1 patients between HCT and non-HCT groups (OS probability at 2-years: 80% vs 68%, respectively, p= 0.182), the 2-year OS was significantly better (p<0.001) in the alloHCT group (67%, n=133) compared with non-HCT group (34%, n=37), when analysis was done in int-2 or high-risk patients. (Figure 1b) In an attempt to further assess the inherent selection bias, we analyzed and compared patients with no available donor (n=29, biologic assignment) with patients who did not receive HCT for other reasons (n=44). No statistically significant difference (p=0.13) was seen in the 2 year-OS (58% vs. 45%).
In conclusion, using a unique cohort of patients who were referred for a donor search, our study in real-world practice demonstrates that transplant eligible MDS patients (at the time of donor search) who do not undergo alloHCT have worse survival outcomes compared to those undergoing transplantation. A prospective biologic assignment study is currently underway by the BMT CTN (#1102) to more definitively determine the impact and relative benefits of alloHCT in patients (≥50 years old) with Int2/high-risk de novo MDS.
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Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Salhotra:Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.
With the adoption of reduced-intensity conditioning (RIC) regimen, allogeneic hematopoietic cell transplantation (alloHCT) is being increasingly used in older adults. However, data are sparse on the ...safety and efficacy of this procedure in patients aged ≥70 years. Currently the majority of these patients receive either non-myeloablative busulfan (Bu; 3.2-6.4mg/kg) or low-dose total body irradiation (TBI; 2-4.5Gy)- based conditioning regimens, which are associated with a relatively high incidence of disease relapse.
We report here the transplant outcomes of patients aged ≥70 years with hematological malignancies who underwent alloHCT with melphalan (Mel)-based conditioning regimen (Mel 100-140mg/m2 plus fludarabine or clofarabine) between May 2007 and September 2016 at City of Hope. We evaluated 53 consecutive patients (median: 71, range: 70-78 years, 35 males and18 females) who underwent AlloHCT for acute myeloid leukemia (n=27), myelodysplastic syndrome (n=14), myeloproliferative neoplasm (n=6), acute lymphoblastic leukemia (n=2), non-Hodgkin lymphoma (n=2), blastic plasmacytoid dendritic cell neoplasm (n=1), or acute promyelocytic leukemia (n=1) from HLA-identical sibling (n=11), matched unrelated donor (8/8, n=38) or mismatched unrelated donor (n=4). Fifty-one patients received peripheral blood stem cell grafts while two received bone marrow grafts. Graft versus host disease (GVHD) prophylaxis was tacrolimus/sirolimus-based in all patients. The disease risk index (DRI) score was high-very high in 36% of patient (n=19) and Karnofsky score was ≥70% in all patients. The HCT comorbidity index was 3 or more in 21 patients.
Fifty-two of our 53 patients achieved neutrophil engraftment with the median time to engraft of 15 days (range: 11-29 days). Blood or bone marrow chimerism analyses showed >95% of patients achieved >95% donor chimerism within 6 weeks from alloHCT, consistent with “semi-ablative” nature of Mel-based RIC. With a median follow up of 22 months (range: 5-99 months), the 2-year overall survival (OS) and progression-free survival (PFS) were 65.8% (95%CI: 49.9-77.7%) and 60.7% (95%CI: 45.2-73.0%), respectively (Figure 1a). Cumulative Incidence (CI) of non-relapse mortality (NRM) at 1 and 2 years were 18% and 18%, and CI of relapse at 1- and 2-years were18.6% and 21.3%, respectively (Figure 1b). 100-day CI of grade II-IV acute GVHD was 37.7% (grade III-IV: 18.9%), and 2-year CI of chronic GVHD was 57% (48% extensive). In multivariate high/very high DRI was the only independent predictor for poor OS was (HR: 3.14, 95%CI: 1.29-7.61, p=0.011).
While clinical outcomes were favorable for the most part, the hospital course was complicated by ICU transfer (24.5%, n=13) and altered mental status or fall requiring CT scan of the brain (24.5%, n=13), with the median duration of hospitalization of 33 days (range: 20-147 days). Blood stream infection (BSI) was developed in 11 patients (21%). Only 2 patients (3.8%) developed probable/proven invasive fungal infection (one patient developed Aspergillus fumigatus and the other patient developed Cryptococcus gatti). While CMV viremia was observed in 13 patients (24.5%) no CMV disease was diagnosed in any of these patients. Of the 49 discharged patients, 48 went home (one to rehab facility).
In conclusion, alloHCT in combination with Mel-based semi-ablative conditioning is associated with acceptable toxicities including NRM, low-risk of relapse, favorable OS and relapse free survival (RFS) in patients ages 70 years and older. Our data collectively suggest that chronological age alone should not exclude patients from undergoing alloHCT, and this treatment should be offered to selected older individuals with hematologic malignancies.
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Nademanee:seattle Genetics: Speakers Bureau. Stein:Stemline: Consultancy; Amgen: Consultancy, Speakers Bureau.
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TRIO has been shown to be associate with higher risk of morbidity (infections, venocclusive disease and hepatic dysfunction) and mortality after allogeneic HCT. A high transplant iron score (>25 ...red cell unit transfused prior to HCT, serum ferritin > 1000 ng/ml and a bone marrow (BM) iron stain of +6) was associated with 50% decrease in survival at one year (Storey J. Hem & Oncol 2009). TRIO in BM macrophages can generate free radicals resulting in oxidant stress thereby altering the hematopoietic microenvironment. This could have adverse effects on hematopoiesis and affect engraftment after HCT. To date, limited data are available on the effect of TRIO on outcomes of UCB HCT. We examined whether TRIO quantified based on serum ferritin (sF) and BM iron score (MIS) impact outcomes of UCB HCT, particularly with regards to engraftment.
We reviewed 150 consecutive patients (pts) who underwent UCB HCT between March 2006 and September 2015 at City of Hope. Median age at time of HCT was 33.5 years (yrs) (range: 0-70 years) with 55% male and 23% < 18 yrs of age. sF was available within 30 days before HCT for 65%, and MIS was assessed on the pre-HCT BM biopsy for 40% of pts. HCT indications included bone marrow failure (n=13), hemoglobinopathies (n=2), lymphoma (n=23), acute leukemia (n=104), and chronic leukemia (n=8). Disease risk index (DRI) was high/very-high in 38% and 20% of pts had HCT comorbidity index of more than 2. One cord graft was received for 20% of pts. Median TNC of 4.9X10^7/kg (range: 1.8-26.6) and median CD34 count of 1.8X10^5/kg (range: 0.2-122.4). HLA match status was 4/6, 5/6, 6/6 in 93, 48, and 9 pts. Almost 60% of pts received myeloablative conditioning regimen (MAC) and 80% had calcineurin inhibitor/mycophenolate mofetil for graft versus host disease (GVHD) prophylaxis.
With a median follow-up of 48.1 months (range: 5.8- 119.6), 2- and 5-yrs progression free survival (PFS) were 41% and 35.5% while 2- and 5-yrs OS were 47% and 36%, respectively. Cumulative incidence (CI) of NRM at 2 and 5 yrs were 35.7 and 40.6% and CI of relapse at 2- and 5-yrs were 23 and 24%, respectively. Day 100 grade II-IV and grade III/IV aGvHD were 56.7% and 28.7%. 2 yrs CI of cGvHD was 51.7% with 38.8% extensive cGvHD. DRI was found to be significant factor for relapse (HR 1.74 95%CI 0.88-3.45 p<0.001) and conditioning regimen significantly affect OS (HR= 1.92 95%CI 1.24-2.96; p=0.003), PFS (HR= 2.12 CI 1.39-3.24; p<0.001) and relapse rate (HR= 4.07 CI 1.95-8.49; p<0.001) when non-myeloablative/reduced intensity conditioning was compared with MAC. However, day 100 grade II-IV and III/IV aGVHD was increased in pts with MAC (65.1% vs 45.3%; p=0.006 and 37.2% vs 17.2%; p=0.005; respectively) with no significant effect seen on the NRM (p=0.9).
In multivariable analysis, sF <1000 ng/ml independently predicted for shorter OS (HR=0.49; CI 0.27-0.88 p=0.015). When the impact of sF was examined by quartiles, pts in the highest sF quartile (>1948 ng/ml) had shorter OS (HR=3.05, 95%CI: 1.40-6.66; p=0.03) and higher NRM (HR=2.79, 95%CI: 1.16-6.72; p=0.03) compared to those in the lowest quartile (<530 ng/ml) (Fig 1a and b). There was no statistically significant difference in regards to disease relapse, or incidence of acute or chronic GVHD across sF groups.
Patients in the highest sF quartile had delayed platelet engraftment compared to those in the lowest quartile (HR=0.46, 95%CI: 0.24-0.89, p=0.03). A trend towards delayed neutrophil engraftment was also observed between these 2 groups (HR=0.57, 95%CI: 0.33-0.99; p=0.055) (Fig 1c and d). No significant difference was seen in neutrophil (p=0.67) or platelet engraftment (p=0.92) based on MIS. But there was a statistically significant increase of grade II-IV aGVHD in pts with MIS of 3-4 (63.8% vs 30.8% at day 100; p=0.04). This however did not translate into worse OS, NRM or relapse.
In conclusion, TRIO measured by sF has an adverse impact on OS and NRM in recipients of UCB HCT. Elevated sF is also associated with delay in platelet and neutrophil engraftment after UCB HCT. MIS was not associated with time to engraftment, however, this value was available in only 40% of pts. Therefore, TRIO should be considered as a risk factor for adverse outcome and poor graft function after UCB HCT.
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Nademanee:seattle Genetics: Speakers Bureau.
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