ObjectiveMeasuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, ...defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5.MethodsTo investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times.ResultsA comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies.ConclusionsThe modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.
CMV-infection is a serious complication in patients after allogeneic stem cell transplantation (SCT) where immunosuppressive therapy and impaired T cell reconstitution result in a high risk for viral ...infections. Monitoring of CMV-virus load by PCR and preemptive therapy are important tools to prevent CMV disease. However, CMV specific cytotoxic T cells (CMV-CTLs) are needed to successfully control CMV-infections. CMV-specific multimers composed of the patients HLA Class I molecule bound to CMV pp65 epitopes give the possibility to monitor CMV-CTLs. Here, we present the case of CMV-reactivation following SCT for AML.
The percentage of CMV-specific CD8+ T cells was determined by flow cytometry and mapped to clinical and laboratory parameters of the patient. CD8+ T cells were detected using CD8-fluorescein isothiocyanate (FITC, Beckman Coulter) antibody and CD3 as a T-cell marker was labeled with CD3-allophycocyanin (APC, MACS Miltenyi Biotec) antibody. CMV-specific CD8+ T cells were detected using the CMV major histocompatibility complex (MHC) with Strep-Tactinphycoerythrin (PE) conjugate (Streptamers, IBA GmbH).
A 60 years old male patient was diagnosed with acute myeloid leukemia (AML) with 95% myeloid blasts in the bone marrow and extramedullary AML manifestations at the time of diagnosis. Following induction therapy the patient was transplanted from a matched unrelated donor. The stem cell recipient as well as his donor had been tested sero-positive for CMV prior to SCT. Within the first month following transplantation, the patient developed an effective CMV specific immunity as seen by high levels of CMV-specific T cells (Figure 1). About three months following transplantation the patient was diagnosed with intestinal GVHD requiring high-dose glucocorticoid treatment. Following steroid exposure, levels of CMV-CTLs dropped and shortly thereafter rising CMV-copy numbers were observed which was accompanied by clinical signs of CMV enteritis. With the administration of antiviral treatment the CMV specific virus load decreased. However, levels of CMV-CTLs remained low, presumably as a result of ongoing steroid exposure.
High levels of CMV-CTLs appeared to control CMV, as seen by a non-detectable virus load in standard PCR testing. The close correlation between the drop in CMV-CTL count and CMV activation highlights the potential of this method to monitor and understand immune responses to CMV following SCT. Of note, early presence of high frequencies of CMV-CTLs did not guarantee CMV-control under steroid exposure as seen in our case. Previous reports have suggested that high dose glucocorticoids may impact CMV-CTLs survival. This is supported by our case, where we see a rapid drop in CMV-CTLs following glucocorticoid exposure. However, the exact molecular mechanisms and more importantly, the predictive value of this finding remain elusive. Furthermore, these data suggest, that patients with ongoing high steroid exposure may not benefit from a transfer of CMV-specific T-cells to control CMV disease.
Further investigations to clarify the potential of CMV-CTL measurements and to understand the effect of steroid exposure at the functional level are warranted. Studies to correlate CMV-CTL counts with the level of immunosuppression and their influence on controlling CMV-disease will follow. In future, this tool could provide a chance to select patients at high risk of CMV reactivation who could profit from an individualized monitoring and early treatment.
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No relevant conflicts of interest to declare.
The treatment success in patients (pts) with acute myeloid leukemia (AML) is very heterogeneous. Cytogenetic and molecular alterations present at diagnosis are strong prognostic factors, which have ...been used to individualize treatment. As shown by several groups, the subgroup of pts with deletion of the short arm of chromosome 17 are at high risk for treatment failure (e.g. Seifert, Leukemia 2009), which persists even after allogeneic hematopoietic stem cell transplantation (HSCT) (Middeke, Blood 2012; Mohr, Br J Haematol 2013). Besides allelic loss of TP53 located on the short arm of chromosome 17, other mechanisms of inactivation have been shown for this key tumor suppressor gene, most importantly missense point mutations or small deletions. These alterations have also been linked to poor outcome in AML after chemotherapy (Grossmann, Blood 2012). Here, we studied the impact of TP53 mutations on the outcome of AML pts with adverse cytogenetic risk treated with HSCT.
We selected AML pts with complex karyotype (CK), monosomy 7, monosomy 5/del5q and/or abnl(17p) who had received HSCT within 3 randomized controlled trials (NCT numbers 00180115, 00180102, and 00180167). All pts were treated with intensive induction chemotherapy and HSCT according to a risk adapted strategy.
Complete sequencing of the TP53coding region was done using next generation sequencing (NGS) on a 454 GS Junior instrument (Roche) using the IRONII-study amplicon panel. Amplicons were generated from genomic DNA isolated at the time of diagnosis. Data analysis was done using the Sequence Pilot software package (JSI Medical Systems), a 10% cut-off was used for mutation calling.
Nonsynonymous mutations were classified into bi-allelic TP53 mutations if detected allelic frequency as determined by NGS was >50% and mono-allelic TP53 mutations for frequencies between 10% and 50%. All samples with synonymous mutations or no detectable mutations according to the predefined cut-off of 10% were classified as TP53wild type (wt).
Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after HSCT were analyzed according to the mutational status.
Samples from 97 pts with AML were analysed, the median age was 51 years (range 18 to 67), 83% suffered from de novo AML, while 13% had sAML and 3% therapy-related myeloid neoplasms. CK and monosomal karyotype (MK) were present in 61% and 42% of the pts, respectively. Twenty-nine pts (30%) had abnl(17p) detected by conventional karyotyping or FISH analysis. Twenty-six pts (27%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining pts received reduced intensity conditioning (RIC). Donors were siblings in 36 pts (37%) and matched or mismatched unrelated donors in all other pts.
Overall, TP53 mutations were found in 40 pts (41%). Twenty-eight (29%) pts had a bi-allelic TP53 mutation while 12 (12%) pts had a mono-allelic TP53 mutation. We identified 15 pts with TP53 mutations without abnl(17p). Four pts with abnl(17p) had wt TP53. Pts with TP53 mutations were significantly older than pts with wt TP53 AML (median age 55 vs. 43, p=.004). Donor type, type of conditioning and the rate of transplantation in first complete remission were not statistically different among pts with or without TP53mutations.
With a median follow up of 67 months the three-year probabilities of OS and EFS for pts with wt TP53 were 33% (95% CI, 21% to 45%) and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (p=.002 and p=.007) for those with mutated TP53, respectively. CIR at three years was 42% for pts with wt TP53 and 60% for those with mutated TP53 (p=.05). NRM was not different in both groups. In multivariate analysis including age, donor type (sibling vs. all other), type of conditioning (RIC vs. MAC) and disease status (CR1 vs. advanced disease) only the TP53-mutation status had a significant influence on EFS (HR=1.72; p=.03). In our analysis, classification according to MK did not significantly influence OS, EFS, CIR or NRM.
In this cohort of pts with cytogenetic adverse risk abnormalities, who had received HSCT, TP53 mutations were present in 41% of the pts. OS and EFS were significantly worse in pts with mutated TP53. Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in pts with adverse karyotype AML.
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No relevant conflicts of interest to declare.
Background: In relapsed or refractory acute myeloid leukemia (AML), long-term disease-free survival may only be achieved with allogeneic hematopoietic stem cell transplantation (HSCT). Within the ...BRIDGE Trial, the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT was studied. Here, we report long-term survival data and the impact of donor availability at the time of study enrollment. The BRIDGE trial (NCT 01295307) was a phase II, multicenter, intent-to-transplant study.
Patients and Methods: Between March 2011 and May 2013, 84 patients with relapsed or refractory AML older than 40 years were enrolled. Patients were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2, days 1-5). Patients with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 on day -2. In patients with partially matched unrelated donors, ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil.
Results: Forty-four patients suffered from relapsed AML and 40 patients had refractory disease. The median patient age was 61 years (range 40 – 75). According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as intermediate I, 17% as intermediate II and 20% as adverse risk.
The overall response rate assessed at day 15 after start of CLARA was 80% (defined as at least a marked reduction in BM blasts or BM cellularity and absence of blasts in the peripheral blood) with 31% of patients having less than 5% BM blasts at that time. Seventeen patients did not respond to CLARA, and were subsequently treated off-study. Due to early death, three patients were not evaluable for treatment response. Overall, 66% of the patients received HSCT within the trial. Donors were HLA-identical siblings in eight cases (14%), HLA-compatible unrelated donors in 30 cases (55%) and unrelated donors with one mismatch in 17 cases (31%). Treatment success was defined as complete remission (CR), CR with incomplete recovery (CRi) or CRchim (BM donor chimerism >95% and absolute neutrophil count >0.5/nL) on day 35 after HSCT. Treatment success was achieved in 61% of the patients. With a median follow up of 25 months, the OS for all enrolled patients at two years was 42% (95% CI, 32% to 54%). (Figure 1) The Leukemia-free survival at two years for those 51 patients who achieved the primary endpoint was 52% (95% CI, 40% to 69%). (Figure 2)
At the time of enrollment, 14% of patients had a related donor and 33% had an unrelated donor available. In 46% of the patients, donor search was initiated at the time of enrollment. For 7% of patients, donor search was unsuccessful prior to enrollment and reinitiated. The OS at 2 years for patients with a related or an unrelated donor available was 75% (95% CI, 54% to 100%) and 47% (95% CI, 31% to 71%), respectively, while it was 29% (95% CI, 18% to 48%) for patients for whom donor search was initiated at time of enrollment (p = .09).
Conclusions:
Salvage therapy with CLARA, and subsequent conditioning with clofarabine and melphalan prior to allogeneic HSCT, provides good anti-leukemic activity in patients with relapsed or refractory AML. Fast unrelated donor search and work up, with conditioning in aplasia allowed a high rate of successful HSCTs. The leukemia-free survival for this group of elderly, high risk AML patients is very promising.
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Middeke:Genzyme: Speakers Bureau. Off Label Use: Clofarabine for AML. Schetelig:Genzyme: Research Funding; DKMS German Bone Marrow Donor Center: Employment.
Abstract 489
Systemic iron overload (SIO) can be frequently encountered in AML and MDS patients (pts) and predominately occurs as a consequence of recurrent red blood cell transfusions (RBC). SIO has ...been associated with an increased risk for infectious complications and acute graft-versus-host disease (aGvHD) as well as with excessive early non-relapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT). However, most of these studies relied on surrogate markers like ferritin and transfusion burden, which might be interference prone in this patient population. Consequently, the prognostic impact of these parameters is under considerable debate and a variety of different thresholds for risk stratification have been proposed. Studies using improved and objective assessments of SIO like magnetic resonance imaging (MRI) are rare and limited in patient number. We aimed at determining prospectively the influence of SIO as quantified by MRI on post-transplant outcome in a large cohort of AML and MDS patients undergoing allo-SCT.
From 2009 on, MRI-based assessment of liver iron content (LIC) according to the methods described by Gandon (Lancet 2004) and Rose (Eur J Haematol 2006) was routinely performed prior to conditioning in all AML and MDS patients at risk for SIO undergoing allo-SCT at our center. Further, serological parameters of SIO were determined at the same time. Post-transplant outcome including the occurrence and extent of GVHD as well as NRM were correlated with variables of SIO. Categorial variables were assessed using Fisher's excact test, while competing events statistics was used to compare cumulative incidences of NRM and aGvHD. Correlations are reported as Spearmans rank correlation coefficient (r).
Over a period of 30 months 59 AML- and 22 MDS patients with a median age of 57 years were prospectively screened with liver MRI. Median LIC was 140 μmol/g (range: 40 – 350 μmol/g). Ferritin was elevated in all patients with a median of 2204 ng/ml (range: 305 – 45049 ng/ml) and patients had received a median of 24 units of packed red blood cells (RBC, range: 4 – 127).
There was a strong positive correlation between transfusion burden and LIC (r = 0.702, p<0.001) as well as between ferritin and LIC (r = 0.594, p < 0.001). A threshold of 20 or more RBC, which is widely accepted as a good marker for SIO, was found to predict an elevated LIC (>=125 μmol/l) with a sensitivity and specificity of 70.0 % and 81.8 %, respectively. Contrasting, the commonly used criterion of ferritin above 1000 ng/ml albeit, being very sensitive (95.5%), provided only very poor specificity (27.0%). Increasing the ferritin threshold to 2500 ng/ml, a level known to correlate with increased NRM, lead to increased specificity 81.1% at the price of moderately reduced sensitivity (63.6%).
None of the three SIO parameters was associated with an increased risk of aGvHD or infections after allo-SCT, while preexisting aspergillosis was more common in iron overloaded patients (LIC >= 125 μmol/g: 33.3% vs. 0.0 %, p <0.001; RBC >=20: 27.1 vs. 3.4%, p = 0.013; Ferritin >= 1000 ng/ml: 21.2% vs. 0.0 %, p = 0.199). A moderate correlation between LIC (r = 0.494, p < 0.001) as well as transfusion burden (r = 0.478, p < 0.001) and the time between diagnosis and allo-SCT was noted, while ferritin was not associated with that parameter. Interestingly, both transfusion burden (r = 0.248, p = 0.026) and ferritin (r = 0.329, p = 0.003) but not LIC showed a weak but significant correlation with hematopoietic transplantation comorbidity scores.
Regarding NRM we were able to show only a modest trend for transfusion burden of 20 or more RBC as a predictor for an adverse prognosis (100 day CI of NRM: 26.2% vs. 7.7%, p = 0.080). Furthermore, ferritin above 2500 ng/ml (CI: 26.0 vs. 13.4%; p = 0.231) did not correlate with NRM. In contrast, an LIC of 125 μmol/g or more, which is known to be associated with organ toxicity in thalassemia patients, predicted for a significantly increased risk of NRM (CI: 30.8 % vs. 6.3%; p = 0.016). Multivariate analysis confirmed LIC but not transfusion burden or ferritin as an independent risk factor for an increased NRM (HR 1.007 for every 1 μmol/g increase, p = 0.022).
We conclude that systemic iron overload is an independent negative prognostic factor for post-transplant outcome in AML and MDS patients but definition of SIO should be based on reliable parameters like MRI- measured LIC.
Wermke:Novartis: Research Funding. Platzbecker:Novartis: Research Funding.
Abstract 2017
In relapsed or refractory AML allogeneic transplantation (HCT) is considered to be the only chance to achieve long-term disease-free survival. However, only about 40% of younger ...patients with relapsed AML receive allogeneic HCT. A number of factors contribute to this low rate. Among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy may prevent from transplantation. Clofarabine is considered to have a favorable risk-benefit ratio in this indication. Therefore, our goal was to study the safety and efficacy of a clofarabine salvage therapy prior to allogeneic HCT (NCT 1295307). Here, we report data from patients of stage I of a two-stage phase II study.
Patients above the age of 40 with relapsed or refractory AML who were fit for allogeneic HCT were eligible to participate in this multicenter, single-arm study. All patients received at least one cycle of clofarabine 40 mg/m2 followed by intermediate dose cytarabine 1 g/m2 days 1–5 (CLARA). Patients with a donor who exposed at least a reduction of leukemic blasts were scheduled for allogeneic HCT in aplasia after CLARA. Patients without a donor should receive consolidation therapy with CLARA. The conditioning regimen started earliest on day 15 after CLARA and consisted of clofarabine 30 mg/m2 on days -6 to -3 and melphalan 140 mg/m2 on day -2 prior to HCT. GvHD prophylaxis consisted of cyclosporine in combination with MMF. In patients with partially matched unrelated donors the administration of a cumulative dose of 4.5 mg/kg ATG (Genzyme) was recommended. Primary endpoint was treatment success defined as a complete remission (CR, CR(i)) six weeks after completion of therapy. Toxicities were graded according to CTCAE Version 3.0.
Twenty-six patients were enrolled into stage I of this trial. Median age was 60 years (range, 40 to 74 years). Fifty percent of the patients each had refractory or relapsed AML. At early response assessment on day 15 after CLARA-1 13 patients (50%) had less than 10% marrow blasts. Ten patients (38%) showed a reduction in marrow cellularity or blast percentage. Two patients did not respond to CLARA and were subsequently treated off study. One patient died on day 18 after the first cycle from septic multi-organ failure. Twenty-two patients (85%) received allogeneic HCT within this trial. Donors were HLA-identical siblings in 5 patients (23%), HLA-compatible unrelated donors in 11 patients (50%) and partially matched unrelated donors with one mismatch in 6 patients (27%).
All 26 patients have been evaluated for the primary endpoint. Sixteen patients had a CR (62%) and 6 patients a CRi (23%) at final response evaluation, all after allogeneic HCT. One patient responded to chemotherapy but needed surgical intervention due to a pulmonary aspergillosis and could not proceed with therapy within the projected timelines and was therefore considered as treatment failure. Liver toxicity was the most frequent adverse event. Seventeen patients (65%) developed grade III liver enzyme elevation considered to be at least possible related to the study drug. Grade IV liver toxicity was observed in 1 patient. Liver injury indicated by elevated transaminases was transient and did not lead to persistent liver damage or hepatic sinusoidal obstruction syndrome. Due to frequently required per-protocol dose reductions of clofarabine prompted by grade III elevations of transaminases the study protocol was amended to a reduced dose of clofarabine 30 mg/m2 in CLARA chemotherapy. Five patients developed grade I/II elevation of creatinine and 2 patients developed renal failure (grade IV) in the context of septic organ failure. Grade I/II hand-foot syndrome occurred in 5 patients. With a maximum follow up of 17 months 14 patients have died (5 patients died after relapse). At present 12 patients are alive, 7 of these are relapse-free, 3 patients are alive with relapse and 2 patients are currently receiving hypomethylating agents for molecular relapse.
Salvage therapy with CLARA and subsequent conditioning with clofarabine and melphalan prior to allogeneic HCT provides good anti-leukemic activity in patients with relapsed or refractory AML. The complete remission rate of the first 26 patients was evaluated favorably and the trial is currently recruiting to reach the total number of 82 patients. Longer follow up is needed to evaluate relapse-free survival.
Middeke:Genzyme: Honoraria. Off Label Use: Clofarabine, not approved for AML. Bornhäuser:Genzyme: Honoraria. Schetelig:Genzyme/Sanofi: Honoraria, Research Funding.
Abstract 4167
Acute graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (HCT) has been classically assumed to be mediated by T helper cells type 1 (Th1), ...characterized by the production of interferon-γ (IFN-γ). Recently, Interleukin 17A (IL-17)-producing CD4+ T helper type 17 (Th17) cells have also drawn attention as possible effector cells of acute GvHD in murine models. Their role following allogeneic HCT in humans is unknown. We hypothesized that IFN-γ/IL-17-production and quantity of T helper cells might depend on the time-point after HCT, immune responses to allo-antigens (GvHD) or pathogens (e.g. bacterial infection, CMV reactivation) and the presence of T cell depleting antibodies (e.g. ATG). To explore this hypothesiswe initiated a prospective study to investigate the reconstitution of Th1, Th1/17 and Th17 cells in patients after HCT.
80 consecutive patients with various hematologic disorders undergoing allogeneic human leukocyte antigen (HLA)-matched HCT at our center between 12/2009 and 9/2010 were included into the study. Blood samples were collected once in the 1st month, 2nd month and 3rd month after HCT. To quantify IL-17- and IFN-γ-producing T helper cells, we used surface staining for CD3 and CD4 followed by intracellular cytokine staining for IFN-γ and IL-17 in PBMCs. T helper cells producing both IFN-γ and IL-17 (IFN-γ+IL-17+) were termed Th1/17 cells, T helper cells producing only either cytokine alone are indicated as Th17 cells (IFN-γ−IL-17+) or Th1 cells (IFN-γ+IL-17−). For each time period patient cohorts were defined according to the subsequent criteria: (i) bacterial infection (C-reactive protein >50 mg/L, positive blood culture and/or fever in the absence of viral or fungal infection), (ii) CMV reactivation (positive CMV-specific PCR), (iii) acute GvHD (according to the Seattle criteria) and (iv) ATG in the conditioning regimen (dose of 20mg/kg on day -3, -2 and -1 before HCT). As a reference group we chose time-matched and age-matched patients that did not meet any of the criteria under investigation. Student′s t test (two sided, unpaired) was used for statistical evaluation.
In all patients with no relevant complication (absence of bacterial infection, CMV reactivation, acute GvHD) and no ATG in the conditioning regimen Th1, Th1/17 and Th17 cells were detectable within the first month after HCT. However, these T helper cell subsets did not reconstitute to levels of healthy controls within the first 3 month after HCT. In contrast to Th1 cells, no further expansion of Th1/17 and Th17 cells was observed following the 1st month after HCT. ATG during conditioning significantly reduced the frequency of Th17 cells at all time-points analyzed (median decrease: 1st month, 71.5%, P=0.0049; 2nd month, 82.5%, P=0.0002; late engraftment, 71.4%, P=0.0011). Th1/17 cells were also suppressed in patients with ATG, although this reduction was less prominent and reached no significance following the 2nd month after HCT (median decrease: 1st month, 76.19%, P=0.012; 2nd month, 70.11%, P=0.054; late engraftment, 50.7%, P=0.69). Finally, Th1 cells were not significantly reduced in patients receiving ATG compared to time-matches controls (median decrease: 1st month: 89.18%, P=0.34; 2nd month: 62.7%, P=0.21; late engraftment: 19.9%, P=0.8), indicating that the suppressive effect of ATG is less pronounced on Th1 and TH1/17 cells, compared to Th17 cells. Acute GvHD°I was not associated with significant changes in the size of the Th1, TH1/17 or Th17 cell subsets. In patients with GvHD°II-IV a tendency towards increased counts of Th1, TH1/17 and TH17 cells in the peripheral blood was observed. However, these changes were not statistically different compared to time-matched controls. CMV reactivation triggered the expansion of all T helper subsets and Th1 cells showed the strongest increase (median increase: Th1, 449.1%, P=0.00075; Th17, 74.9%, P=0.00069; Th1/17, 97.1%, P=0.00012). In contrast, no significant changes were found in the T helper cell compartment of patients with bacterial infection compared to time matched controls.
In conclusion, quantitative reconstitution of Th1, Th1/17 and Th17 cells is impaired within the first 3 months after HCT, especially when ATG is administered during conditioning. CMV reactivation, but not bacterial infection, triggered the absolute expansion of these T cell subsets.
No relevant conflicts of interest to declare.
Abstract 3493
An increased risk for GvHD, infections and liver toxicity after transplant has been attributed to iron overload (defined by serum ferritin) of MDS and AML patients prior to allogeneic ...hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, the reason for this observation is not very well defined. Consequently, there is a debate whether to use iron chelators in these patients prior to allo-HSCT. In fact, serum ferritin levels and transfusion history are commonly used to guide iron depletion strategies. Both parameters may inadequately reflect body iron stores in MDS and AML patients prior to allo-HSCT. Recently, quantitative magnetic resonance imaging (MRI) was introduced as a tool for direct measurement of liver iron. We therefore aimed at evaluating the accurateness of different strategies for determining iron overload in MDS and AML patients prior to allo-HSCT.
Serologic parameters of iron overload (ferritin, iron, transferrin, transferrin saturation, soluble transferrin receptor) and transfusion history were obtained prospectively in MDS or AML patients prior to allo-SCT. In parallel, liver iron content was measured by MRI according to the method described by Gandon (Lancet 2004) and Rose (Eur J Haematol 2006), respectively.
A total of 20 AML and 9 MDS patients (median age 59 years, range: 23–74 years) undergoing allo-HSCT have been evaluated so far. The median ferritin concentration was 2237 μg/l (range 572–6594 μg/l) and patients had received a median of 20 transfusions (range 6–127) before transplantation. Serum ferritin was not significantly correlated with transfusion burden (t = 0.207, p = 0.119) but as expected with the concentration of C-reactive protein (t = 0.385, p = 0.003). Median liver iron concentration measured by MRI was 150 μmol/g (range 40–300 μmol/g, normal: < 36 μmol/g). A weak but significant correlation was found between liver iron concentration and ferritin (t = 0.354; p = 0.008). The strength of the correlation was diminished by the influence of 5 outliers with high ferritin concentrations but rather low liver iron content (Figure 1). The same applied to transfusion history which was also only weakly associated with liver iron content (t = 0.365; p = 0.007). Levels of transferrin, transferrin saturation, total iron and soluble transferrin receptor did not predict for liver iron concentration.
Our data suggest that serum ferritin or transfusion history cannot be regarded as robust surrogates for the actual iron overload in MDS or AML patients. Therefore we advocate caution when using one of these parameters as the only trigger for chelation therapy or as a risk-factor to predict outcome after allo-HSCT.
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No relevant conflicts of interest to declare.
In relapsed or refractory acute myeloid leukemia (AML) long-term disease-free survival may only be achieved with allogeneic stem cell transplantation (HSCT). However, only about 40% of patients (pts) ...with relapsed AML receive HSCT. A number of factors contribute to this low rate, among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy. Clofarabine is considered to have a favorable risk-benefit ratio in this indication and has been successfully used in conditioning regimens. Our goal was to study the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT. Here, we report the results of the BRIDGE trial (NCT 01295307), a phase II, multicenter, intent-to-transplant study.
Between March 2011 and May 2013, 84 pts with relapsed or refractory AML older than 40 years were enrolled. Pts were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2 days 1-5). Pts with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2 day -6 to -3 and melphalan 140 mg/m2 on day -2. In pts with partially matched unrelated donors ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil.
Median age was 61 years (range 40 – 75). Forty-four pts suffered from relapsed AML and 40 pts had refractory disease. According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as interm. I, 17% as interm. II and 20% as adverse risk. Complex and monosomal karyotypes were present in only 12% and 10% of pts, respectively. FLT3, NPM1 and CEPBA mutations were found in 16%, 24%, and 4% of the pts. The mean value of the HCT-CI score was 1.6 (range 0 - 7) at the time of study enrollment and 2.3 (range 0 - 7) at the time of conditioning.
The overall response rate assessed at day 15 after start of CLARA was 80% (46% good response defined as less than 10% blast in the bone marrow (BM) and 33% moderate response with at least a marked reduction in BM blasts or BM cellularity and absence of blast in the peripheral blood). Seventeen pts did not respond to CLARA and were subsequently treated off study. Due to early death, three pts were not evaluable for treatment response. Overall, 66% of the pts received HSCT within the trial. Donors were HLA-identical siblings in eight pts (14%), HLA-compatible unrelated donors in 30 pts (55%) and unrelated donors with one mismatch in 17 pts (31%). Treatment success defined as complete remission, CR with incomplete recovery or >95% BM donor chimerism and an absolute neutrophil count >0.5 /nL on day 35 after HSCT was achieved in 62% of the pts. Disease-free survival (DFS) is shown in Figure 1. With a median follow up of 16 months the OS for all enrolled patients at one year is 51% (95% CI, 39% to 63%).
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At the time of enrollment, 14% had a related donor and 33% had an unrelated donor. In 46% of the pts donor search was initiated at the time of enrollment. For 7% of pts donor search was not successful. Time from study entry to HSCT was remarkably low with a median of 33 days (range 19 – 116 days). Of note, time interval did not differ between related and unrelated donors (Figure 2).
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Day 30 and day 100 mortality, which covered salvage therapy and HSCT, was 9% and 27%, respectively. Six out of seven pts who died within the first 30 days hat refractory AML and thus entered the trial already with a history of long-lasting neutropenia. Liver toxicity was the most frequent adverse event. Fifty percent of the pts had transiently elevated liver enzymes CTCAE grade III considered to be related to clofarabine. Twenty-one patients developed CTCAE grade III – IV sepsis throughout the study treatment. GvHD grade II – IV and III-IV until day 100 after HSCT occurred in 36% and 21% of the pts, respectively.
This intent-to transplant study allows for a realistic estimate for the outcome of elderly pts with relapsed or refractory AML. We demonstrate a high rate of leukemia-control by CLARA. Fast unrelated donor search and work up and conditioning with clofarabine and melphalan in aplasia allowed for a high rate of successful HSCTs. While the long-term results require longer follow-up the overall results are promising.
Middeke:Genzyme: Speakers Bureau. Schetelig:Genzyme: Research Funding. Off Label Use: Clofarabine, not approved for AML.
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