Stem Cell Transplantation For Acute Myeloid Leukemia Research Articles

Incidental association: Acute myeloid leukemia and filariasis - A case report

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the abnormal proliferation of myeloid cells in the bone marrow. Symptoms include fatigue, frequent infections, easy bruising or bleeding, and shortness of breath. Filariasis is a parasitic infection caused by filarial worms (a nematode) transmitted through mosquito bites from infected individuals, leading to chronic lymphatic dysfunction, lymphedema, hydrocele, and elephantiasis. Here, we present the case of a 38-year-old male who was diagnosed with acute myeloid leukemia without maturation (M1) and an incidental finding of microfilariae in a peripheral blood smear. Interestingly, there was no accompanying eosinophilia in this case. This coexistence of filariasis and AML poses diagnostic challenges, as eosinophilia may not be a reliable indicator. Treatment options include Diethylcarbamazine, Ivermectin, Albendazole and Doxycycline for filarial and chemotherapy and stem cell transplantation for AML (M1). The prognosis for the patient is poor.

The Impact of Pre-Transplant Extramedullary Disease on the Outcome of Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Children- on Behalf of PDWP/EBMT

Background Extramedullary disease (EMD), including central nervous system (CNS) and myeloid sarcoma, is a rare presentation in Acute Myeloid Leukemia (AML). We studied the effect of EMD (CNS involvement only and other EMD ± CNS) compared to isolated BM involvement in the outcomes following hematopoietic stem cell transplantation for AML in children. Methods An EBMT registry-based retrospective study to assess the impact of extramedullary disease (EMD) in children (de novo AML, age <18y at transplant, period 2008-2016) with AML who underwent a first allogeneic hematopoietic cell transplant (allo-HCT) with non-TBI conditioning regimen. Outcomes of interest included: leukemia-free survival (LFS), overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM). Patients were grouped into three categories: BM involvement only (Group A), BM+CNS involvement only (Group B) and BM+ other EMD ± CNS (Group C). Patients with Down syndrome related AML and t(15:17) AML were excluded. Results A total of 958 (529 males) patients met study criteria, including 685 (71.5%) Group A, 135 (14.1%) Group B and 138 (14.4%) Group C patients. Group C patients were transplanted at a younger age (median age at transplant 4.8y vs 9.2y and 6.6y for Group A, B respectively, p <0.001). A higher proportion of Group A patients were in CR1 (70.8%) compared to Group B (63.7%) and C (60.1%) patients. The three groups were comparable regarding the distribution of high and standard risk cytogenetics. Fifty seven percent of the patients received an unrelated donor and 35% a matched sibling/family donor. The median post HCT follow-up was 5.4 years (IQR: 5.2-5.7y). Five years LFS, OS, RI and NRM were 62%, 68.4%, 26.4% and 11.6%, respectively in the entire cohort. Multivariate analysis showed higher RI in Group C compared to Group A (HR= 1.45 (1.01-2.06) p=0.04) and a non-significantly different NRM (HR: 0.61 (0.29-1.29), p=0.2). There was no difference in RI in Group B compared to Group A (Hazard Ratio (HR) : 1.12 (0.76-1.64). In the multivariate analysis patients with EMD (CNS only or EMD+/- CNS) had no significant difference in LFS, OS and NRM. The Hazard ratio of LFS, OS and NRM for Group B and C compared to Group A was: HR=1.13, p= 0.46; HR=0.96, p=0.82; HR=1.09, p=0.76 and HR=1.19, p=0.28; HR=0.96, p = 0.82; HR=0.61, p=0.2, respectively. Further 116 patients underwent hematopoietic stem cell transplantation with active disease. Eighty-nine patients had BM involvement only (group A), 12 patients had BM and CNS disease (Group B) and 15 patients had BM and other sites of EMD +/- CNS (Group C). In this cohort, the 4y-OS was 37% in Group A, 25% in Group B of and 38% in Group C. Four-year LFS was 31%, 25% and 39% in Group A, Groups B and Group C respectively. Conclusions Our findings suggest that children with AML and BM with EMD ± CNS involvement (group C) have a higher incidence of relapse after HCT compared to those with BM only or BM+CNS only disease. However, the presence of EMD with CNS involvement or other extramedullary disease did not have a statistically significant impact on overall survival, leukemia-free survival or non-relapse mortality. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Efficacies of FLT3 Inhibitors in Patients with Acute Myeloid Leukemia.

FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations.

Impact of prior solid tumor on outcomes of allogeneic hematopoietic stem cell transplantation for AML or MDS.

7048 Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a definitive treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Prior solid tumor (PST) is felt to portend a worse post-transplant prognosis. The aim of this study was to evaluate the impact of PST history on allo-HSCT outcome. Methods: We retrospectively identified patients with AML or MDS who underwent first allo-HSCT at the Fred Hutchinson Cancer Research Center between 2010 and 2018. Cox regression analysis was used to identify factors associated with mortality among patients with PST, and to compare outcomes of patients with and without PST. Multivariable models were fit, adjusting for cytogenetic risk level, time from PST diagnosis to transplant, receipt of reduced-intensity conditioning (RIC), and age at transplant. Survival estimates were obtained using the Kaplan-Meier method. Results: 1198 patients were included for analysis, of which 101 had a history of PST. After a median follow up of 1301 days among survivors, there was a total of 558 deaths and 322 relapses among all patients. Patients with history of PST were older (62.5 vs 54.9 yrs) and a higher proportion received RIC (52.5% vs 27.3%). The most common PSTs included breast (38/101, 38%), prostate (13/101, 13%), colon (9/101, 9%), thyroid (8/101, 8%), and uterine (7/101, 7%). Among those with known staging (n = 66), stage 1 (28/66, 42%) was the most common, followed by stage 2 (17/66, 26%) then stage 3 (15/66, 23%). The most common therapies provided were surgery (95/101, 95%), cytotoxic chemotherapy (41/101, 41%), radiation (45/101, 45%), and endocrine therapy (25/101, 25%). The unadjusted hazard ratio (HR) of mortality in the PST group relative to the non-PST group was 1.10 (95% confidence interval [CI] 0.83-1.47, p = 0.52). After adjustment for patient age, disease, patient/donor CMV status, KPS, cytogenetic risk, source of stem cells, and donor type, the adjusted HR was 0.91 (95% CI 0.68-1.22, p = 0.59). The unadjusted HR for relapse was 1.15 (95% CI 0.79-1.67, p = 0.48), and adjusted HR was 1.11 (0.76-1.11, p = 0.61). Among patients with PSTs, high-risk cytogenetics were associated with increased mortality (adjusted HR = 2.21; 95% CI 1.16-4.2, p = 0.016) and relapse (adjusted HR = 1.91; 95% CI 1.01-3.60, p = 0.047). Longer time from PST diagnosis to transplant led to a numerically increased mortality in the unadjusted (HR = 1.05; 95% CI 1.00-1.11, p = 0.057) and adjusted (HR = 1.05; 95% CI 1.00-1.11, p = 0.69) models treating time as a continuous linear variable. Conclusions: In our study, a history of PST did not impact overall survival or relapse rate among patients who underwent first allo-HSCT for AML or MDS. As in the overall population, post-transplant outcomes were primarily driven by cytogenetic risk level. However, it is likely that selection of patients with PST for transplantation was biased based on overall risk assessment.

Comparison of Melphalan Combined with Treosulfan or Busulfan as High-Dose Chemotherapy before Autologous Stem Cell Transplantation in AML.

Simple SummaryDifferent consolidation strategies are available for acute myeloid leukemia (AML) patients fit for intensive treatment. For favorable- or intermediate-risk AML, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is one of these options. Busulfan plus melphalan is a frequently used and efficient HDCT regimen, but it bears neurotoxic potential and may cause irreversible alopecia, amongst other toxicities. Thus, improving HDCT regimens with lesser toxicity, albeit at comparable anti-leukemic efficacy, is wishful. We combined treosulfan with its more favorable toxicity profile with melphalan for HDCT and compared these patients with a group receiving busulfan/treosulfan. Whereas disease-free and overall survival did not differ significantly, the treosulfan regimen compared favorably, with the absence of neurotoxicity and irreversibly alopecia. Treosulfan serum levels by mass cytometry demonstrated considerable interindividual biovariability. Further studies should explore treosulfan/melphalan for HDCT/ASCT in AML, aiming to improve the quality of life of AML survivors and offer safer consolidation strategies.(1) Background: High-dose chemotherapy (HDCT) before autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) patients predominantly combines busulfan with cyclophosphamide or melphalan. Treosulfan compares favorably regarding lower inter-individual bioavailability and neurotoxicity, but so far, had not been studied before ASCT in AML. (2) Methods: This single-center study investigated AML patients undergoing ASCT in CR1 between November 2017 and September 2020. The first 16 patients received busulfan 16 mg/kg b.w. (days −5 to −2) and melphalan 140 mg/m2 (day −1) (BuMel). In a subsequent (TreoMel) cohort, 20 patients received treosulfan 14 g/m2 (days −4 to −2) and melphalan. Plasma concentrations of busulfan and treosulfan were determined by mass spectrometry. (3) Results: Neutrophil engraftment and platelet recovery were similar, and PFS and OS were comparable. In only the BuMel cohort, patients reported central nervous toxicities, including seizures (6%) and encephalopathy (12%). The mean AUC for busulfan was 1471.32 μM*min, and for treosulfan it was 836.79 mg/L*h, with ranges of 804.1–2082 μM*min and 454.2–1402 mg/L*h. The peak values for busulfan ranged between 880.19–1734 μg/L and for treosulfan between 194.3–489.25 mg/L. (4) Conclusions: TreoMel appears to be safe and effective for pre-ASCT treatment in AML patients. Due to considerable interindividual biovariability, pharmacologic monitoring may also be warranted for the use of treosulfan.

Pembrolizumab in Combination with Antigen-Specific Cytotoxic T Lymphocytes Enhances Killing of Acute Myeloid Leukemia

BackgroundPembrolizumab, an antibody that blocks programmed cell death protein 1 (PD-1), has been FDA approved for several solid tumors and hematologic malignancies. Currently, pembrolizumab is under investigation for acute myeloid leukemia (AML) in combination with hypomethylating agents. It is established that AML is highly responsive to immunotherapy, as seen with the anti-leukemic effect of allogeneic hematopoietic stem cell transplantation (alloHSCT). However, response to cytotoxic T lymphocytes (CTLs) that target leukemia-associated antigens (LAAs) has been less reliable in eradicating disease. This insufficient response to LAA-specific CTLs is likely partially accounted for by the immune dysregulation seen in AML. Because of promising murine data that blockade of the PD1/PD-L1 pathway enhances the graft versus leukemia effect of alloHSCT, we investigated if adding pembrolizumab to CTLs that target the two LAAs CG1 and PR1 will enhance CTL antileukemia activities. CG1 and PR1are two HLA-A2 restricted nonameric peptides that we validated as promising AML targets derived from cathepsin G (i.e. CG1), and proteinase 3 (P3) and neutrophil elastase (NE) (i.e. PR1). We hypothesized that pembrolizumab added to CG1-CTLs and PR1-CTLs, will enhance their anti-leukemic effects with minimal off target toxicities.MethodsUsing a standard calcein AM in vitro cytotoxicity assay, we co-cultured AML targets, including U937 HLA-A2 + (U937-A2) AML cell line and primary patient HLA-A2 + AML samples, with CG1-CTL and PR1-CTL. AML cells were loaded with calcein AM and then incubated with CG1- and PR1-CTLs at increasing effector to target ratios. Pembrolizumab or isotype antibody were added to the cultures. After 4 hours, calcein AM was measured to determine cell viability. T2 cells pulsed with PR1 or CG1, were used as a positive control and non-pulsed T2 cells were used as negative control cells. For in vivo experiments, we used a human established AML xenograft mouse treatment model to determine the effect of pembrolizumab when added to CG1- or PR1- CTL in vivo. CG1-CTL and PR1-CTLs were expanded from the same donor and used as the effector cells. NOD/SCID gamma (NSG) mice (4-6-week-old females) were engrafted with AML samples by tail vein injection. After confirming engraftment, CG1- and/or PR1-CTL were administered to mice and pembrolizumab or isotype antibody [100ug/mouse] were given three times over two weeks. Mice were monitored for clinical GVHD and AML three times/week. Mice were sacrificed at approximately two weeks following treatment. To assess for GVHD, mouse tissues including spleen, liver, kidney, BM, intestine, brain, heart, and lung were harvested and fixed in 10% formalin. The fixed tissue samples were embedded in paraffin, sectioned, and stained with hematoxylin and eosin prior to histologic examination. Bone marrow (BM) was processed using standard methodology and analyzed for residual AML by flow cytometry.Results:In vitro our data demonstrate that U937-A2 and two primary patient HLA-A2 AML samples, have enhanced cell lysis when treated with pembrolizumab (CTL+ pembrolizumab) in comparison with isotype (Iso) + CTL, pembrolizumab only, iso only or CTL only groups (Figure 1). In vivo data show a decrease in U937-A2 disease burden and primary patient AML after treatment with CG1and/or PR1-CTL (CTL-treated) . This decrease was enhanced when pembrolizumab was added to the CTL-treated mice (CTL+ pembrolizumab) in comparison with mice treated with pembrolizumab only (pembrolizumab-treated), or CTL only (CTL-treated) (Figure 2). Pathology data to assess toxicity in mice treated with CTL +/- pembrolizumab showed an enhanced pulmonary (perivascular and parabronchial) lymphocytic infiltration in mice treated with the combination of CTL and pembrolizumab. The other organs investigated, showed no change when combination therapy was used.Conclusion:We have validated in vitro and in vivo the enhanced killing of AML (cell lines and primary patient samples) by CG1-CTL and/or PR1-CTL after addition of pembrolizumab. Toxicity data show mild enhancement of lymphocytic infiltrate in the lungs after addition of pembrolizumab to CTL. Our data suggest that the strategy of combining LAA-specific CTL with immune checkpoint blockade could prove beneficial in the setting of adoptive T cell therapy and allogeneic stem cell transplantation for AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia with Monosomy 7 or Deletion 7q: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

▪ INTRODUCTIONMonosomy 7 or deletion 7q (-7/7q-) is the most frequent high-risk cytogenetic feature reported in acute myeloid leukemia (AML) and is associated with a dismal outcome after chemotherapy alone. Allogeneic stem cell transplantation (SCT) appears to be the best consolidation strategy in these patients (pts), thereby significantly improving outcomes. Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion/translocation of chromosome 3q26 (inv(3)). The presence of such abnormalities may further influence the outcomes of SCT in pts with -7/7q-. The purpose of this study was to evaluate the role of SCT in AML with -7/7q- in the context of additional cytogenetic abnormalities. METHODSWe selected adult pts with AML and -7/7q- reported to the EBMT registry with a complete cytogenetic report. We included only first SCT from a sibling or unrelated donor (UD) performed between 2000 and 2016. RESULTSA total of 1109 pts were identified. Median age at SCT was 52 year-old (range, 18-76) and median follow-up was 34 months (range, 0.7-193). A diagnosis of secondary AML was reported in 213 pts (19%). At the time of SCT, 702 patients (63%) were in first remission (CR1), 58 (5%) in subsequent remission and 349 (32%) had active disease. Four hundred ninety-six pts received SCT from a sibling donor (45%). Most pts had a Karnofsky's performance status (KPS) of more than 80% at the time of SCT (93%). A myeloablative conditioning regimen was administered in 50% of the pts. In vivo T-cell depletion was part of the regimen in 56% of the pts.The 2-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. The 2-year probability of non-relapse mortality (NRM) was 20% and the 2-year cumulative incidence of relapse (RI) was 50%. The cumulative incidence of acute graft-versus-host disease (GvHD) was 31% and the 2-year cumulative incidence of chronic GvHD was 31%. The 2-year probability of GvHD and relapse-free survival (GRFS) was 21%. In multivariate analysis, age was not associated with any outcomes. Active disease was significantly associated with increased NRM and RI, which translated into worse LFS, OS and GRFS. Significant higher NRM was associated with UD. Secondary AML was associated with higher NRM and decreased OS. Better KPS correlated significantly with less NRM and better LFS, OS and GRFS.To evaluate the impact of additional cytogenetic abnormalities, we have been able to sort out 5 different groups within the entire cohort. The first group included 523 pts with -7/7q- with or without CK, but without any of the following chromosomal abnormalities: MK, -5/5q-, abn(17p) or inv(3). One hundred ninety-nine pts belonged to the second group that included pts with -7/7q- within MK but without -5/5q-, abn(17p) or inv(3). The third group included 151 pts with -7/7q- in association with -5/5q- but no abn(17p) or inv(3). Group 4 included 125 pts with -7/7q- and abn(17p) but without inv(3). Finally, 111 pts had inv(3) in addition to 7/7q- and were assigned to the fifth group. NRM was similar across all groups. The 2-year probability of LFS was 39.7% for group 1, 28.5% for group 2, 22.5% for group 3, 16.4% for group 4 and 13.7% for group 5 (p<0.001) (see figure). The 2-year probabilities of OS in the 5 groups were 47.7%, 34.9%, 28.2%, 15.9% and 19.7%, respectively (p<0.001). The corresponding 2-year probability of GRFS was 29.7% for group 1, 16.6% for group 2, 14.5% for group 3, 8.1% for group 4 and 8.9% for group 5 (p<0.001). Multivariate analysis confirmed those significant differences across groups. We observed comparable results when the analysis was focused on CR1 pts. CONCLUSIONSSCT in AML pts with -7/7q- provides durable response in one third of the pts. Disease status at the time of transplantation remains the strongest prognostic factor for poor outcomes. The presence of -7/7q- with or without CK in the absence of MK, -5/5q-, abn(17p) or inv(3) was associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of pts that benefits less from SCT. In these pts, future efforts should focus on prevention of relapse by therapeutic modalities like early withdrawal of immunosuppression, administration of hypomethylating agents, donor lymphocytes infusion or others. [Display omitted] DisclosuresSocié:Alexion Pharmaceuticals, Inc.: Consultancy. Mohty:Sanofi: Honoraria, Speakers Bureau.

Significance of Marker Chromosome on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for AML

Significance of Marker Chromosome on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for AML

An Anti-CD300f Antibody Drug Conjugate Depletes Hematopoietic Stem Cells and Primary Acute Myeloid Leukemia (AML): Facilitating a Targeted Conditioning Regimen for Allogeneic Stem Cell Transplantation in AML

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) significantly reduces the rate of relapse in Acute Myeloid Leukemia (AML) but comes at the cost of significant Treatment Related Mortality (TRM). Despite the reduction in relapse overall, it remains common, especially in high risk groups. There is increasing evidence that many cases of relapse are driven by residual AML that can be detected with minimal residual disease techniques. A large proportion of the morbidity that prevents most patients accessing allo-HSCT is due to nonspecific toxic conditioning agents which are required to remove recipient Hematopoietic Stem and Progenitor Cells (HSPC) allowing for successful engraftment. We propose that a targeted conditioning agent against AML and HSPC can facilitate a reduction in relapse and TRM in allo-HSCT. CD300f is expressed evenly across HSPC subtypes. CD300f has equivalent transcription and protein expression as CD33 on AML. We have developed an anti-CD300f antibody which efficiently internalises into target cells. Harnessing this ability to internalise, we have generated a highly potent anti-CD300f Antibody Drug Conjugate (ADC) with a pyrrolobenzodiazepine (PBD) warhead which selectively depletes AML cell lines in vitro. Colony Forming Units were inhibited when cultured in the presence of the ADC. The anti-CD300f ADC has a rapid onset of action with >99% cytotoxicity of the AML cell line HL-60 occurring within 24 hours. The ADC synergises with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. The growth of subcutaneous tumours in mice engrafted with the AML cell line U937 was significantly reduced by a single dose of our ADC (at 150 μg/kg or 300 μg/kg). In a bone marrow engraftment model with HL-60, our ADC prolongs the survival at a single dose of 300 μg/kg (Fig 1A). In a humanised mouse model, 85% of all CD34+ cells and 90% of the primitive CD34+ CD38- CD90+ population were depleted with a single injection of our ADC at 300 μg/kg (Fig1 B). There was significant reduction in primary AML cells with a single injection of our ADC at 300 μg/kg (Fig 1C). This proof of principle work establishes an anti-CD300f ADC as an attractive potential therapeutic to develop which will reduce the toxicity of allo-HSCT and the relapse rate afterwards. We have demonstrated that CD300f is expressed across HSPC and AML. Our antibody to CD300f is efficiently internalised and capable of delivering a PBD warhead. Our ADC synergised with fludarabine and has a rapid onset of action. We have demonstrated that our ADC prolongs survival in mouse cell line models as well as depletes both HSPC and primary AML in vivo. A targeted conditioning agent has the potential to reduce relapse risk and toxicity of allo-HSCT in AML.

The Induction of a Permissive Environment to Promote T Cell Immune Evasion in Acute Myeloid Leukemia: The Metabolic Perspective.

Acute myeloid leukemia (AML) is the acute leukemia with highest incidence amongst adults. Despite significant improvements in understanding the genomic landscape and the introduction of novel drugs, long-term outcome remains unsatisfactory. Recently, immunotherapeutic approaches have heralded a new era in cancer treatment. The success of allogeneic hematopoietic stem cell transplantation in AML highlights the disease's immunoresponsiveness. Several immunotherapeutic applications are currently under clinical evaluation and include immune checkpoint blockades, T cell-engaging antibodies, and genetically engineered T cells. However, immunoevasive mechanisms employed by AML blasts severely hamper our endeavors. A better understanding of the underlying mechanisms remains a prerequisite for improving treatment efficacy. One of the hallmarks of the cancer cells is metabolic reprogramming, introduced by Otto Warburg's seminal studies during the beginnings of the last century. Nowadays, it is well established that metabolic adaptation is not just an epiphenomenon during oncogenesis but rather a necessity for tumor development and progression. Furthermore, accumulating data suggest an important role of aberrant tumor cell metabolism for immune escape. AML blasts display a number of metabolic alterations that could be linked to immunoregulation, and these include competition over substrates, abundant release of bioactive metabolites, and an overall microenvironmental metabolic re-modeling that favors the induction or survival of immunoregulatory cell subsets such as regulatory T cells. In this review, we outline the immunoevasive character of the AML blasts' bioenergetics, set it into context with oncogenic mutations, and discuss potentially suitable countermeasures and their limitations.

Survival after Post-Hematopoietic Stem Cell Transplantation AML Relapse: A Single Center Experience

Introduction Post-allogeneic hematopoietic stem cell transplantation (HSCT) acute myeloid leukemia (AML) relapse has a dismal prognosis and no standard of care treatment. Current common treatment options for (re)inducing a graft versus leukemia effect (GvL) are cessation of immunosuppressive therapy, administering hypomethylating agents or high dose chemotherapy. After reinduction of remission is achieved, the effect can be consolidated with a donor lymphocyte infusion (DLI) or a second allogeneic HSCT. In this study we analyzed outcomes of patients with post-allogeneic HSCT AML relapse in our institute. Objectives To evaluate outcome of patients with post-allogeneic HSCT AML relapse, who received different types of reinduction therapy regimens and of whom a subgroup underwent immunological consolidation therapy. Methods Data was collected from the medical history of all 83 adult patients that had received an allogeneic stem cell transplantation for AML or high-risk myelodysplastic syndrome (MDS) at the Amsterdam University Medical Centers between January 1st 2010 and 31st December 2016 and who relapsed before December 31st 2017. In this retrospective analysis, patients were divided into a curative intent treatment group and a palliative care group. Statistical analysis was done with IBM SPSS version 24.0.0.1 using Mann-Whitney U, Chi-square testing, Pearson's R for ordinal variables and Kaplan Meier survival analysis with log rank testing. Results 50 (60%) of the 83 patients were treated with the intent to cure and the other 33 (40%) received palliative care. Of the patients treated with curative intent, 13 (26%) survived. The patients in the palliative care group were older than the patients in the curative intent group (median age 58 vs 53 year, P=0.043). They also had a higher bone marrow blasts count (median 37.5% vs 20.5%, P=0.025), and shorter time between allo HSCT and relapse (median 21 weeks with IQR of 6-28 vs median of 21 weeks with IQR 14-47.25, P=0.047). Within the curative intent group these variables did not differ significantly between survivors and deceased. Of the patients in the curative intent group 44% reached CR and of these patients 50% survived. The majority of the survivors received high dose cytarabine treatment (69%) and immunologic consolidation therapy (69%). A relapse ≤ 12 weeks after allogeneic HSCT but not relapse Conclusion This retrospective analysis of a real-life, non-preselected patient group with post-allogeneic HSCT AML or MDS relapse demonstrated that patients who were fit enough to receive high-dose reinduction therapy, followed by a immunologic consolidation with DLI or a second allogeneic HSCT had the best chance to obtain durable remissions, in particular when immunologic consolidation was performed when the patient had obtained complete remission.

It's Not All in the Conditioning or the Perils of Early Trial Cessation

It's Not All in the Conditioning or the Perils of Early Trial Cessation

Clinical Features and Prognosis of Unselected Patients with AML and RAEB-2: Japan Adult Leukemia Study Group CS-07 Study

[Background] In practice, the clinical features of acute myeloid leukemia (AML) and refractory anemia with excess blasts-2 (RAEB-2) are much more heterogeneous than cases selected in clinical trials. It is also not easy in prospective trials to evaluate the efficacy of allogeneic stem cell transplantation during the first remission for AML, since the selection of treatment is not random but is mostly dependent on the donor availability. In Japan Adult Leukemia Study Group CS-07 study, we tried to see the real world of AML and RAEB-2 in Japan, aiming to see the prognosis and the applicability of known prognostic factors for cases in practice, and to address the efficacy of allogeneic stem cell transplantation for AML during the first remission. [Methods] All AML and RAEB-2 cases that were diagnosed at participating institutions were prospectively registered between Mar 2003 and December 2011. Data of 3054 patients from 117 institutes were updated as of June 2016. [Results] Male patients were predominant (n=1,944); female (n=1,100). Mean age at the diagnosis was 61.3 years (range, 15 to 96 years), and the disease type was diagnosed as de novo, secondary, and therapy-related in 2,255, 593, and 206 patients, respectively. Among 2937 patients with available cytogenetic data, 517, 1626, and 794 patients were classified in the favorable-, intermediate-, and adverse-risk group, respectively. Transplantation was performed in 23.3% of cases, and 39.8% were done during the first remission. For AML, the 3- and 5-year overall survival rate (OS) was 36.3% (SE 1.0%) and 32.5% (SE 1.0%), and those for RAEB-2 were 19.4% (SE 2.2%) and 13.3% (SE 4.2%), respectively. OS in favorable-, intermediate-, and adverse-risk group were 89.6% and 80.6%, 75.4% and 48.2%, and 39.7% and 17.3%, respectively, for younger patients (P<.001), and were 69.0% and 56.5%, 49.1% and 37.3%, and 18.9% and 3.7%, respectively, for elderly patients (P<.001). Age group was significantly related with the clinical results. To address the efficacy of allogeneic transplantation during the first remission, the propensity score analysis was performed making nested pairs in these registered cases, in which transplantation did not demonstrate the significant improvement of OS.[Conclusion] The result of this study would mirror the overall features of AML and RAEB-2 patients in our country, and confirmed the prognostic values of age group, and cytogenetic risk not only in younger but also in elderly patients. The usefulness of allogeneic stem cell transplantation for AML during the first remission needs to be addressed further in "real world" situation. DisclosuresAoyama:Alexion: Honoraria. Kiyoi:Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Celgene Corporation: Consultancy. Kobayashi:SymBio Pharmaceuticals: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Ariad: Research Funding. Naoe:Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Pfizer Inc.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Celgene K.K.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria.

An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia.

Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.

Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) has not been widely used in patients with acute myeloid leukemia (AML) and Down syndrome (DS) due to fear of transplantation-related toxicity. A retrospective analysis of the outcome of allogeneic HSCT was conducted in 15 patients with AML and DS. The five patients transplanted with the reduced intensity conditioning (4 in complete remission (CR) and 1 in non-CR) had a significantly better survival rate than 10 patients transplanted with a conventional conditioning (4 in CR and 6 in non-CR) (3-year EFS (95% confidence interval): 80.0% (20.4-96.9%) vs. 10.0% (0.6%-35.8%), P = 0.039).

Influence Of Steroid Exposure On CMV Specific T Cells Following Allogeneic Stem Cell Transplantation

IntroductionCMV-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. MethodsThe 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). CaseA 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. DiscussionHigh 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. ConclusionFurther 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. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Rare Extramedullary Relapse of Acute Myeloid Leukemia Manifested as Granulocytic Sarcoma of the Breast: Imaging Findings and Pathology Correlation

We present two cases of granulocytic sarcoma of the breast in women who had a prior history of Acute Myeloid Leukemia (AML). Both patients presented with a palpable breast mass (one patient with a right breast mass and the other patient with bilateral breast masses) within one year following allogeneic peripheral blood stem cell transplantation for AML. Ultrasound-guided biopsy of the breast masses showed granulocytic sarcoma, a rare tumor without obvious primary bone marrow involvement. Reports of bilateral breast involvement with granulocytic sarcoma following allogeneic peripheral blood stem cell transplantation for AML are rare. Granulocytic sarcoma should be considered in the differential diagnosis of a new palpable breast mass in patients with a history of malignant hematologic tumor treated by allogeneic peripheral blood stem cell transplantation.

Bone Marrow Cellularity, but Not Dysplasia, Is An Additional Prognostic Factor for Patients with Acute Myeloid Leukemia After Allogeneic Stem Cell Transplantation

Abstract 4467 Background:Relapse incidence (RI) and non-relapse mortality (NRM) are competing risks limiting overall survival (OS) after allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Disease and transplant specific factors predicting relapse like measurement of minimal residual disease (MRD) and chimerism analysis are widely used to aid prophylactic and preemptive treatment decisions. Prediction of NRM mostly relies on pretransplant features. Although most transplant centers routinely perform bone marrow (BM) cytomorphology after SCT for AML, the impact of factors beyond blast count is not well studied. Study Design:We analyzed frequencies and prognostic impact of dysplasia and cellularity upon BM cytomorphology of 112 patients (60 m/52 f, median age 53 [range 17–72] years) with AML at 1st manifestation/ relapse at day 30 (d30) and day 100 (d100) after SCT. Using peripheral blood as main graft source (n=106), donors were unrelated in 87 cases, related in 25. Conditioning was reduced (RIC, n=72) or myeloablative (MAC, n=40). All patients received G-CSF from day 5 until stable engraftment was achieved. Dysplasia was assessed following WHO criteria with different thresholds (10%, 20%, 50%) to define a hematopoietic lineage as dysplastic. We performed a correlation of dysplasia and age-adapted cellularity with outcome measures, calculating RI and NRM as competing risks. Only patients who achieved blast clearance on d30 after SCT were included in the study. Patients who developed hematological relapse between d30 and d100 were only evaluated for d30. At d30 (d100), BM aspirates from 75 (65) patients were available for morphologic evaluation. Result:Dysplasia was a frequent event both at d30 and d100, with ≥10% dysplastic features in granulopoiesis in 25.0% of cases at d30 (31% d100), in erythropoiesis in 34.6% of cases at d30 (43.6% d100) and in megakaryopoiesis in 47.7% of cases at d30 (63.5% d100). Overall, cellularity at d30 was increased in 17.3% (d 100: 6.5%), reduced in 37.3% (d100: 38.7), and normal in 45.3% (d100: 54.8%). No significant correlation with CMV reactivation or with the type of immunosuppression (cyclosporine/ methotrexate versus cyclosporine/ mycophenolic acid) was noted. Cumulative incidences of 2-year-RI and 2-year-NRM were 34% (95% CI, 24%-44%) and 17% (95% CI, 9%-25%). Dysplasia both at d30 and d100 did not correlate with OS or RI. Yet, a statistically significant correlation of normal overall cellularity at d30 with less relapses (RI 20.6%) when compared with reduced overall cellularity (RI 32.1%) or increased overall cellularity (RI 76.9%; p=0.001) was observed. Estimated 2-year-OS was 59% in pts with normal overall cellularity versus 31.4% (reduced) and 44.0% (increased), respectively (p=0.009). The same results, favoring normal cellularity, were observed for each lineage (granulopoiesis, erythropoiesis, megakaryopoiesis). Conversely, increased overall cellularity at d30 correlated with lower NRM (8.3%) when compared to normal (NRM 23.7%) and reduced overall cellularity (NRM 39.6%, p=0.031). Thus, whereas reduced overall cellularity at d30 correlated both with higher RI and higher NRM, the impact of increased cellularity on survival was less clear. The analysis of subdistributive hazards in the competing risk factor model revealed a cumulative RI of 62% (95%CI 35%-89%, HR 6.68, p=0.00014) for increased cellularity, making it the most potent hazard in this analysis. Presence of an informative sample was of prognostic value, too (2-year-OS/ NRM 54.7%/ 80.4% for “evaluable” versus 20%/ 36.9% for “not evaluable” due to low cellularity, p<0.001). Cellularity at d100 showed no significant correlation with survival outcomes. We found no correlation of either dysplasia or cellularity with the pretransplant cytogenetic risk group and CMV serostatus. In this study, patients with AML who achieved normal cellularity early in the post-transplant period had improved survival outcomes and a reduced relapsed incidence as compared to patients with abnormal cellularity in bone marrow aspirates. Conclusion:These data suggest that cellularity of BM cytomorphology at d30 after allogeneic SCT aids to assess risk of relapse and NRM in transplant recipients with AML. At this time, it can only be speculated whether underlying persistent leukemia below the microscopic level might be associated with disturbed BM cellularity. Disclosures:Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Role of Second Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Hematologic Malignancies

Prognosis of patients relapsing after stem cell transplantation (SCT) is poor if no further treatment is given. A second SCT is a limited option in these high-risk patients. We retrospectively analyzed the outcomes of second SCT in acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia after a first SCT. Twenty-five of 30 patients received second allogeneic SCT. Variables related to survival were disease status before second allogeneic SCT and time interval between transplants more than 1 year ( P < .01 and P < .02 in multivariate analysis). Treatment-related mortality was 33% with no impact of the conditioning regimen on overall survival. Second allogeneic SCT in selected patients may be an option in this group with a poor outcome.

Recent advances in the treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) is a disorder with significant molecular and clinical heterogeneity. Although there have been clear advances in the identification of somatic genetic and epigenetic alterations present in the malignant cells of patients with AML, translating this knowledge into an integrated view with an impact on the clinical treatment of AML has been slower to evolve. Recent clinical advances in the treatment of AML include studies demonstrating the benefit of dose-intense daunorubicin therapy in induction chemotherapy for patients of any age. We also review use of the DNA methyltransferase inhibitor azacitidine for treatment of AML in elderly patients as well as a study of global patterns of DNA methylation in patients with AML. Lastly, we review a recent assessment of the role of allogeneic hematopoietic stem cell transplantation in AML in first complete remission.