Abstract 3841
The International Prognostic Scoring System (IPSS) has recently been revised (IPSS-R) to capture more inclusive cytogenetic characterization, more stringent blast description, and more ...detailed cytopenia assignments. To validate the IPSS-R in a prospective cohort of patients, we compared IPSS and IPSS-R categorization within a group of newly diagnosed MDS patients in a prospective population-based epidemiologic study in Minnesota.
We identified all newly diagnosed MDS cases in Minnesota between the ages of 20 and 85 years from April 1, 2010 to April 2012. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), patient contact and enrollment, central medical review including: 1) independent review by two hematopathologists to confirm diagnosis and WHO subclassification; 2) independent cytogeneticist's review for classification as defined by IPSS and IPSS-R; and 3) medical chart review with prospective calculation of IPSS, IPSS-R, and WPSS by a an oncologist.
Classification of the 128 patients by IPSS versus IPSS-R is shown (Table)IPSS-R dxTotalVery LowLowIntermediateHighVery HighIPSS dxLow161910036INT-1410138035INT-2008172550High000077Total2029222532128
Kendall's Tau = 0.77
In this comparative classification, IPSS-R scoring refined the MDS prognostic risk groups. Low IPSS remained low risk in the IPSS-R spanning the Very Low and Low groups, while all high risk IPSS remained in the Very High risk group in the IPSS-R. However, those in the INT-1 and INT-2 IPSS categories were inconsistently reclassified in the IPSS-R. INT-1 IPSS spanned from Very Low to High and INT-2 IPSS spanned from Intermediate to Very High in the IPSS-R. While reclassification of this prospective cohort resembles results in the IPSS-R reports, ongoing follow-up will be needed to determine if the survival and AML progression measures are reproducible.
Until molecular data are available to refine future prognostic scoring systems, the IPSS-R enhances our prognostic risk stratification abilities and is applicable to the general MDS population. As treatment decisions are based on this initial prognostic risk assessment, the more diverse differentiation of risk within the IPSS-R will directly refine prognosis and impact decisions on therapy.
Miller:Celgene: Membership on an entity's Board of Directors or advisory committees; Coronado Bioscience: Membership on an entity's Board of Directors or advisory committees.
Abstract 3049
Despite rapid advances in allogeneic hematopoietic cell transplant (HCT) techniques, the procedure continues to be associated with a high morbidity and mortality with transplant related ...mortality (TRM) ranging from 15% to as high as 50%. Acute graft versus host disease (GvHD) remains a major cause of morbidity and an important cause of early TRM in patients undergoing allogeneic HCT. Though variations in major histocompatibiliy (MHC) genes are well known determinants of acute GvHD, there is increasing evidence that genetic variation in immune/cytokine response pathways also contributes significantly to the pathogenesis of acute GvHD.
We evaluated the association of single nucleotide polymorphisms (SNPs) in non-MHC dependent immune/cytokine response pathways (n= 77 SNPs in recipients and donors) with acute GvHD and TRM at one year in a cohort of 425 recipient-donor pairs who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota between 1998 and 2007. We used a Fine and Gray proportional hazards model adjusted for competing risk to evaluate the association between the genetic variants and time to acute GvHD and time to TRM.
After adjustment for recipient age at transplant, race, diagnosis, disease status at transplant, gender mismatch, CMV serostatus of recipient and donor, recipient and donor sex, donor type, conditioning regimen (myeloablative or reduced intensity) and year of transplant, one recipient SNP, rs646005 in the TIRAP gene and one donor SNP, rs2232596 in the LBP gene were marginally associated with increased risk for grade II-IV acute GvHD (Hazard ratio (HR) = 1.33 (95% Confidence interval (CI): 1.07 – 1.62) and 1.32 (1.07 – 1.66) respectively; p =0.01). Similar analyses for TRM showed recipient SNP rs5498 in the ICAM1 gene was associated with a decreased risk of TRM (HR: 0.67(95% CI: 0.50 – 0.89); p=0.0006) while recipient SNPs rs1739654 in the LBP gene and rs3804100 in the TLR2 gene were associated with an increased TRM risk (HR: 1.86 (95% CI: 1.16 – 2.97) and 1.66 (95% CI: 1.11 – 2.48) respectively; p =0.01).
These findings are consistent with previous reports that support a role for genetic variants in the innate immune response pathways among both recipients and donors can influence the risk of acute GvHD and TRM among patients undergoing allogeneic HCT. These findings indicate that a systematic search for genetic variants in the innate immune response pathways may identify novel biomarkers that can be used to identify patients at high risk for acute GvHD and TRM.
Weisdorf:Genzyme: Consultancy, Research Funding.
Abstract 2027
The identification of minimal residual disease (MRD) can predict impending relapse in acute myeloid leukemia (AML) patients. Little data exists evaluating the prognostic impact of MRD, ...as determined by multiparametric flow cytometry (MFC), at the time of allogeneic (allo-HCT). Although disease outcomes may be worse for MRD positive (MRD+) patients, MRD is often associated with other adverse risk factors leaving it unclear whether MRD is an independent risk factor for relapse or a surrogate marker for underlying poor risk disease features.
We retrospectively analyzed 97 consecutive AML patients in complete morphological remission (CR) who underwent allo-HCT with a matched related donor (MRD, n=30, 31%), matched unrelated donor (MUD, n=4, 4%) or umbilical cord blood (UCB, n=63, 65%) at the University of Minnesota between January 2005 and June 2009. Presence of MRD at allo-HCT was determined by MFC. Analyses were done separately for myeloablative (MAC) and reduced intensity conditioning (RIC) patients, testing the impact of MRD along with conditioning intensity, age, donor type and disease status on allo-HCT outcomes.
Of 97 patients, 41 (42%) had MAC; 57 (58%) had RIC. Sixty-six were in first CR (CR1) with the rest in CR2 or later remission (CR2+). MRD at allo-HCT was detected in 7 patients after MAC (17%) and 7 after RIC (12.5%); and this frequency was similar in patients in CR1 and CR2+ (13% vs. 16%, p=0.7). MRD+ and MRD- patients had similar median age (40 vs. 44 yrs), gender, donor source (MSD or MUD vs. UCB), CMV serostatus and diagnostic cytogenetic risk group. Six of 40 (15%) intermediate and 5 of 39 (13%) high risk cytogenetics patients had MRD+ (p=0.8). Only 3 of 53 patients with a cytogenetic abnormality at diagnosis had it detected prior allo-HCT and 1 of 3 had MRD.
The median follow-up of survivors was 25 months. Two-year probabilities for MAC and RIC patients were similar: Overall survival (OS), 48% and 47 % and leukemia free survival (LFS) 43% and 41% respectively. When disease outcomes were analyzed separately by MRD status (table), OS and LFS were markedly worse in MRD+ patients receiving RIC, but this difference was not statistically significant. In multivariate analysis, MRD+ was not an independent prognostic factor for OS and LFS. Although we identified no adverse prognostic factors for MAC patients, patient with RIC in CR2+ had worse OS and LFS vs. CR1 (HR 2.6, p=0.04 and HR 2.7, p=0.04 respectively).
The negative prognostic impact of MRD was overcome by allo-HCT with MAC, but outcomes with MRD+ were suggestively inferior after RIC. However due to limited sample size, MRD in patients with RIC should be further investigated.
2 year outcomesMRD+ (95% CI)MRD− (95% CI)pMACOS43% (10%–73%)49% (32%–65%)0.7LFS43% (10%–73%)44% (27%–60%)0.6RICOS14% (7%–46%)51% (36%–65%)0.1LFS14% (7%–46%)44% (29%–58%)0.1
Weisdorf:Genzyme: Consultancy, Research Funding.
The interactions of variable killer-cell immunoglobulin-like receptors (KIR) with polymorphic HLA class I ligands form an extraordinary immunogenetic system that influences NK cell biology, human ...susceptibility to disease, and the outcome of hematopoietic cell transplantation (HCT). The independent segregation of KIR and HLA genes, on chromosomes 19 and 6, respectively, increases the functional diversity of the system. Previously we found that patients undergoing unrelated donor (URD) HCT for acute myelogenous leukemia (AML) had superior leukemia-free survival (LFS) and less relapse with KIR B/x genotype donors than with KIR A/A donors. At higher resolution we identified the significant protective effect of donors with “Better” (≥2 B-motifs) and “Best” (≥2 B-motifs with Cen-B/B) KIR gene content compared to “Neutral” (0 or 1 B-motif) donors, supporting a donor selection strategy that is being tested in an ongoing prospective multicenter trial. The heterogeneity of transplant cohorts (preparative regimens, graft source, T cell depletion, HLA match status) has complicated the evaluation of the mechanisms underlying the beneficial effects mediated by NK cells. We analyzed 2404 URD transplants for AML and found a strong interaction between the protection associated with KIR B donors and the conditioning intensity (myeloablative MA vs. reduced intensity RI) for relapse (p=0.0002) and LFS (p=0.043). “Better” and “Best” donors were associated with significantly enhanced LFS and relapse protection in MA transplants, but appears to have an opposite effect in RI transplants. Therefore, to further explore the mechanisms of NK cell mediated protection, we focused our evaluation on a cohort of 1007 MA, T cell replete URD transplants for AML. We evaluated the interaction of donor KIR with recipient and donor HLA C1, C2 and Bw4. Superior LFS (RR 0.78 0.66-0.92, p=0.0024) and relapse protection (RR 0.50 0.38-0.67, p<0.0001) were observed with “Better+Best” donors (n=299) compared to “Neutral” donors (n=656). The benefit associated with “Better+Best” donors was enhanced in recipients expressing 1 or 2 HLA-C allotypes carrying the C1 epitope (C1/x (n=245) vs. C2/C2(n=51)) (RR 0.65 0.41-1.01); p=0.05). No significant beneficial interactions were found between donor KIR and donor HLA-C group KIR ligands or with recipient or donor Bw4. Importantly, we did not identify any specific KIR B-haplotype defining gene as associated for the LFS advantage and relapse protection observed in C1/x recipients compared to C2/C2 recipients. Individual analyses for KIR B/x donors with or without 2DS1, 2DS2, 2DS3, 2DS5, 2DL2, 2DL5, 3DS1 showed equally significantly improved outcome (RR ranged from 0.71-0.80, p=0.002-0.03 for LFS and RR 0.56-0.63; p=0.0003-0.0008 for relapse). There was no clinical advantage of any KIR B genes in C2/C2 recipients. Importantly, the components of the relapse protection associated with interactions between “Better+Best” donors and C1/x recipients may depend upon the HLA-match status of the transplant. (P=0.018 for the interaction). In the <10/10 HLA-matched transplants (n=513), the “Better+Best” donors conferred potent relapse protection in C1/x (n=122) vs. C2/C2 (n=28) recipients (RR 0.35 0.16-.76; P <0.01) (Figure 1; right). This relapse protection, of equivalent strength in HLA-C or other HLA mismatches, resulted in improved LFS (RR 0.55 0.34-.90; P=0.02). Conversely, in the 10/10 HLA-matched transplants (n=494), treatment related mortality (TRM) was reduced when “Better+Best” donors could engage recipient HLA-C1 (n=123, RR 0.40 0.20-.0.81; P=0.01) although LFS was not statistically different, due in part to a lack of enhanced relapse protection (RR 3.00 0.69-13.01; P=0.14)(Figure 1; left). Interactions between KIR B-haplotype donors and homozygous C1/C1 in the recipient were associated with less acute GVHD when all transplants were analyzed. In summary, analysis in this homogeneous cohort demonstrates that the outcome of URD transplantation for AML is improved by interactions between recipient HLA-C1 and “Better+Best” KIR donors, which reduce relapse in <10/10 HLA-matched and reduce TRM in 10/10 HLA-matched transplants. This protection is observed in MA but not RI conditioning, suggesting that NK cell reconstitution and function differs in these settings.
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No relevant conflicts of interest to declare.
Abstract 3531
Reduced intensity conditioning (RIC) umbilical cord blood (UCB) transplantation is increasingly used in hematopoietic stem cell transplantation (HCT) for older and medically unfit ...patients. Data on the efficacy of HCT after RIC relative to myeloablative conditioning (MAC) are limited. We compared the outcomes of acute myeloid leukemia (AML) patients > 18 yrs who received UCB grafts after either RIC or MAC.
One hundred nineteen adult patients with AML in complete remission (CR) underwent an UCB transplant after RIC (n=74, 62%) or MAC (n=45, 38%) between January 2001 and December 2009. Conditioning was either reduced intensity and consisted of cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2 and total body irradiation (TBI) 200 cGy or myelablative and consisted for cyclophosphamide 120 mg/kg, fludarabine 75mg/m2 and TBI 1200–1320cGy. All patients received cyclosporine (day -3 to day +180) and mycophenolate mofetil (day -3 to day +45) post-HCT immunosuppression and hematopoietic growth factor. Use of RIC was reserved for patients >45 years (n=37, 82%) or pre-existing severe co-morbidities (n=8, 18%). The two groups were similar except RIC had more preceding myelodysplastic syndrome (RIC=28% vs. MAC=4%, p<0.01) and older age (median, RIC=55yrs vs. MAC=33yrs; p<0.01). Remission status (CR1; RIC=65% vs. MAC=56%, p=0.9), CR1 duration ≥ 1 yr for CR2 HCT (RIC=46% vs. MAC=45% p=0.9) and the HCT-comorbidity index were similar (score >2; RIC=50% vs. MAC=40%, p=0.1). Furthermore, most patients received double UCB graft (RIC=85% vs. MAC=89%, p=0.5) with a maximum HLA disparity of 4/6 and 5/6 in 52% and 34% of RIC recipients vs. 62% and 29% of MAC recipients (p=0.5).
Median follow-up for survivors was 4.2 (RIC) and 3.5 years (MAC). The 3-year leukemia-free survival (LFS) was 31% vs. 55% (p=0.02) and 3-year relapse incidence was 43% vs. 9% (p<0.01) in recipients of RIC and MAC, respectively (Figure). One-year transplant related mortality (TRM) was similar (RIC=16% vs. MAC=24%; p=0.55). In multivariate analysis (Table), RIC recipients and those in CR2 with short CR1 duration had higher risk of relapse and poorer LFS. No factors predicted TRM.
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Table:Multivariate analysis of outcomesOutcome measureRelative risk95% CIpRelapse incidenceRIC vs. MAC4.72.0–10.4<0.01CR11.00CR2 w/ CR1< 1 yr1.91.0–3.80.06CR2 w/ CR1>=1 yr0.50.2–1.50.2Leukemia free survivalRIC vs. MAC2.31.3–4.0<0.01CR11.00CR2 w/ CR1< 1 yr1.91.1–3.40.03CR2 w/ CR1>=1 yr0.70.3–1.40.33
UCB with RIC extends the use of allogeneic HCT for older and less fit patients with limited TRM. However, the increased relapse risk and poorer LFS in the RIC setting indicates the need for novel strategies to improve leukemia control post-transplantation, especially in CR2 patients with short CR1 duration.
Wagner:CORD:USE: Membership on an entity's Board of Directors or advisory committees; VidaCord: Membership on an entity's Board of Directors or advisory committees. Weisdorf:Genzyme: Research Funding; Hospira.
Abstract 1462
NK cells are the first lymphocyte subset to reconstitute following hematopoietic stem cell transplantation (HSCT) and they play a pivotal role in mediation of the graft versus leukemia ...(GvL) effect in myeloid leukemia. We hypothesized that for NK cells to mediate GvL, they must be fully functional via a process termed “licensing” or “education”. Although it has been presumed that NK cell functions (cytotoxicity and cytokine production) develop in parallel through interactions with their class I recognizing inhibitory receptors, new data suggests that this may not be the case. To address this issues we developed a 9-color flow cytometric-based assay to simultaneously measure both CD107a expression and IFNy production by CD56+ NK cells in the context of expression of inhibitory receptors for self-class I human leukocyte antigen (HLA). We tested a cohort of 30 patients who received either unmanipulated (T cell replete) or potently T cell depleted (CD34+ selected) grafts from adult unrelated donors. Thawed peripheral blood mononuclear cells (PBMC) were rested overnight in cytokine free media and then incubated with K562 cells to trigger cytotoxicity and cytokine production. PBMC were stained with CD107a (a surrogate for cytotoxicity), IFNy, CD56, CD3, CD45, CD158a, CD158b, CD158e and CD159a simultaneously. The same normal volunteer and the actual transplant donor were used as positive controls in each assay. Cytotoxicity or IFNy production was calculated as a percentage of the normal positive control. Cytotoxicity was intact but modestly suppressed (∼35%) at 3 months after both T cell deplete and T cell replete HSCT with further recovery of killing at 6 months. By contrast, at 3 months after T cell replete HSCT there was potent and sustained suppression of IFNy production by CD56+ cells (57%±11% suppression, p=0.009). The cohort of patients receiving T cell deplete (CD34-selected) grafts also exhibited significant suppression of IFNy at 3 months after HSCT (73%±9.6%, p=0.018), suggesting that the use of post-transplant immune suppression medications did not explain the effect. Suppression of IFNy production when exposed to targets continued through 6 months post-transplant in both cohorts and was partially restored with low concentrations of IL-15. Cells stimulated overnight with IL-12 and IL-18 produced IFNy at 3 and 6 months. Thus the cells were not globally hyporesponsive, suggesting the defect was based on physiologic interactions with the target. NK cells become educated following engagement of inhibitory receptors (eg. Killer-immunoglobulin-like receptors KIR) with self class I HLA. Therefore we compared NK cells that expressed at least one KIR with KIR negative NK cells. At 3 months post transplant, KIR expression had no effect on cytotoxicity. In contrast, KIR positive cells produced significantly higher amounts of IFNy than KIR negative cells at 3 (Figure 1) and 6 (data not shown) months post-transplant. Therefore following HSCT, expression of KIR discriminates a population of NK cells that produce IFNy, but does not correlate with cytotoxicity. While NK cell cytotoxicity is only partially suppressed following HSCT, IFNy production is significantly reduced. Consistent with this we found that while all IFNy producing cells degranulate, only a small fraction of CD107a+ cells also make IFNy. This effect is not a result of post-transplant immune suppression or graft versus host disease, as patients receiving CD34+ selected grafts had neither. Perhaps NKG2A, highly expressed on almost all NK cells early after transplant, selectively mediates education for cytotoxcity. In conclusion, our data shows distinct defects in NK cell education for either cytotoxicity or cytokine production. This highlights the importance of analyzing both cytotoxicity and cytokine production when assessing NK cell function post HSCT. Because of their critical anti-tumor and infection protection roles, methods to enhance broad in vivo NK cell function, such as the use of post-transplant IL-15 administration, are warranted.
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No relevant conflicts of interest to declare.
We studied whether early cyclosporine A (CsA) trough levels were associated with the risk of acute graft-vs.-host disease (GVHD) in 337 patients after either sibling peripheral blood stem cell or ...double umbilical cord blood transplantation. All patients, regardless of donor type, started CsA at a dose of 5 mg/kg IV divided twice daily, targeting trough concentrations 200–400 ng/ml. The CsA level was studied by a weighted average method calculated by giving 70% of the weight to the level that was measured just prior to the onset of the event or day +30. We found that higher weighted average CsA trough levels early post-transplantation contributed to lower risk of acute GVHD, and lower non-relapse and overall mortality. Thus, our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels in the first weeks of allo-HCT. In patients who are near or even modestly above the CsA target trough level, in the absence of CsA related toxicity, dose reduction should be cautious in order to avoid subtherapeutic drug levels resulting in higher risks for acute GVHD.
Abstract Various cytogenetic risk scoring systems may determine prognosis for patients with myelodysplastic syndromes (MDS). We evaluated 4 different risk scoring systems in predicting outcome after ...allogeneic hematopoietic cell transplantation (alloHCT). We classified 124 patients with MDS using the International Prognostic Scoring System (IPSS), the revised International Prognostic Scoring System (R-IPSS), Armand's transplantation-specific cytogenetic grouping, and monosomal karyotype (MK) both at the time of diagnosis and at alloHCT. After adjusting for other important factors, MK at diagnosis (compared with no MK) was associated with poor 3-year disease-free survival (DFS) (27% 95% confidence interval, 12% to 42% versus 39% 95% confidence interval, 28% to 50%, P = .02) and overall survival (OS) (29% 95% confidence interval, 14% to 44% versus 47% 95% confidence interval, 36% to 59%, P = .02). OS but not DFS was affected by MK at alloHCT. MK frequency was uncommon in low-score R-IPPS and IPSS. Although IPSS and R-IPSS discriminated good/very good groups from poor/very poor groups, patients with intermediate-risk scores had the worst outcomes and, therefore, these scores did not show a progressive linear discriminating trend. Cytogenetic risk score change between diagnosis and alloHCT was uncommon and did not influence OS. MK cytogenetics in MDS are associated with poor survival, suggesting the need for alternative or intensified approaches to their treatment.
Abstract No clear dosing guidelines exist for cyclophosphamide (Cy) dose adjustments in obese patients treated with high-dose chemoradiotherapy followed by autologous hematopoietic cell ...transplantation (HCT). We prospectively compared the outcomes of high-dose Cy/total body irradiation (TBI) conditioning in 147 non-Hodgkin lymphoma (NHL) patients in 3 weight groups: nonobese (<120% ideal body weight IBW; n = 72), overweight (120% to 149% IBW; n = 46), and obese (≥150% IBW; n = 29). Nonobese and overweight patients received Cy (120 mg/kg of total body weight, intravenously) and TBI (1320 cGy), whereas obese patients (median body mass index, 36) received an adjusted Cy dose based on IBW plus 50% of the difference between total body weight and IBW (AdjBW50). The median patient age was 57 years (range, 19 to 73). The most common diagnoses were diffuse large B cell lymphoma (n = 57) and mantle cell lymphoma (n = 51). Three-year overall survival was 61% (95% confidence interval CI, 48% to 72%) for nonobese patients, 68% (95% CI, 52% to 82%) for overweight patients, and 80% (95% CI, 62% to 93%) for obese patients. Cumulative incidence of relapse (48%, 43%, and 38%, respectively) and nonrelapse mortality (∼4%) were similar in all groups. Hemorrhagic cystitis and cardiac toxicity were rare events. Our data show that the AdjBW50 formula can be safely and effectively used for Cy dose adjustments in obese patients treated for NHL with high-dose Cy/TBI conditioning followed by autologous HCT.
Abstract Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are ...associated with allogeneic hematopoietic cell transplantation (HCT) outcomes. Recipient (n = 437) and donor (n = 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and K2). HCT outcomes for mthap matched siblings (n = 198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR = 3.0; 95% confidence interval CI, 1.2 to 7.9; and RR = 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR = 2.1; 95% CI, 1.1 to 2.4) with no events for those with K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7-fold (1.2 to 6.2) increased risk of death in 5 years, whereas few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.
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