Wilms' tumor gene 1 (WT1) is overexpressed in leukemia and WT1‐derived CD8+ T‐cell epitopes for immunotherapies targeting WT1 have been defined. Here, we analyzed expression of WT1 in 226 peripheral ...blood and bone marrow samples from patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) before and after allogeneic stem cell transplantation (SCT). Transcripts were assessed by quantitative polymerase chain reaction, and WT1‐specific CD8+ cytotoxic T cells (CTL) were monitored by tetramer staining and enzyme‐linked immunospot (ELISPOT) assays. Reduction of WT1 levels correlated with a longer survival (p < 0.01). Increment of WT1 transcripts eventually resulted in relapse and subsequent death of the patients. In patients with longer survival and continuous complete remission (cCR) after SCT, higher and enduring frequencies of WT1‐specific CTL than in patients developing a relapse were detected. These cells were effector T cells secreting interferon gamma and granzyme B. In summary, WT1 is a suitable marker for the detection of minimal residual disease after SCT or chemotherapy. A rising WT1 signal correlated with a dismal prognosis of the patients. WT1‐specific CD8+ T cells might contribute to the maintenance of a cCR. Targeting WT‐1 by peptide/protein vaccination as well as adoptive transfer of genetically modified T cells are future options in the individualized therapy for AML/MDS patients.
What's New?
Wilms’ tumor gene 1 (WT1) is overexpressed in a variety of cancers, including acute myeloid leukemia (AML), where WT1 is a considered to be a promising marker for the assessment of minimal residual disease (MRD). That idea is backed here by data showing that WT1 expression following chemotherapy or allogeneic stem cell transplantation in patients with AML or myelodysplastic syndrome (MDS) correlates with survival. Patients with longer survival times and continuous complete remission also exhibited strong CD8+ T‐cell responses against WT1 gene products. The findings suggest that WT1 is a favorable immunotherapeutic target for AML/MDS.
Introduction
MEL at the dose of 200 mg/m2 (MEL200) is considered the standard conditioning regimen before ASCT in MM patients (pts). Lower doses of 140 mg/m2 (MEL140) or 100 mg/m2 (MEL100) are used ...when toxicity is a concern. Whether these lower doses are equally effective is still a matter of debate and available data are conflicting.
Aims and Methods
To compare full dose with reduced dose MEL, we performed a retrospective analysis on MM pts in all disease stages treated at Jena University Hospital between 2003 and 2017. Statistical analysis included descriptive statistics and Cox regression. Progression free survival (PFS) and overall survival (OS) were calculated from the time of ASCT. Here, preliminary data on 187 pts are presented. For pts receiving more than one ASCT (n=69), only data on the first ASCT were included in the analysis. Pts treated with MEL140 and MEL100 were pooled (MELRed group).
Results
Of 187 ASCTs, 163 were performed as first-line and 24 as salvage therapies. Median follow up of the entire population was 77 months (range 3-172). Induction treatment included at least 1 novel agent (immunomodulatory drugs, IMiDs or proteasome inhibitors, PI) in 119 pts, whilst 68 pts received conventional chemotherapy. Median number of induction cycles before ASCT was 3 (range 1-10). Prior to ASCT 31 pts (17%) had achieved at least a very good partial remission (VGPR). MEL200 was used in 112 (60%) and MELRed in 75 pts (40%, 72 MEL140 and 3 MEL100). There was no difference in the two groups in the number of transplant performed as first line or as salvage therapy (p=0.54), as well as in the rate of pts achieving at least a VGPR before ASCT (17% vs. 16%, for MEL200 and MELRed respectively, p=0.84). More pts treated with MEL200 received induction treatment containing novel agents (70% vs. 55% for MEL200 and MELRed respectively, p=0.037). High quality responses (≥VGPR) after ASCT were higher in the MEL200 group: 89% of pts treated with MEL200 vs. 73% of those receiving MELRed, p=0.005. The main reasons for MEL dose reduction were older age (40%) and renal insufficiency (29%). Median age (range) and creatinine values (range) were 55 (35-68) vs. 63 (47-70) years (p<0.001) and 73 (51-186) vs. 90.5 (51-1022) μmol/l (p<0.001) for MEL200 and MELRed, respectively. More pts in the MELRed group had a Charlson Comorbidity Index (CCI) >2 (83% vs. 99% for MEL200 and MELRed respectively, p=0.001). Toxicities and duration of hospitalization of the two groups are depicted in Table 1. The higher response rate seen in pts treated with MEL200 translated in a longer median PFS (43 vs. 27 months for MEL200 and MELRed respectively, p=0.023) and OS (66% vs. 51% at 5 years for MEL200 and MELRed respectively, p=0.046). Multivariate analysis included CCI >2, response before and after ASCT ≥VGPR, disease stage at ASCT, age >65 years, treatment with new drugs, glomerular filtration rate ≥60 ml/min at the time of ASCT and treatment with MEL200. Disease stage (HR 0.57, 95% CI 0.331-0.978, p=0.041) and MEL200 (HR 0.49, 95% CI 0.295-0.802, p=0.005) were associated with an improved PFS, whilst none of the above mentioned variables had an impact on OS.
Conclusion
In comparison with MELRed, MEL200 provides favorable responses and improves PFS and OS with only moderate increase of toxicity in this retrospective pts cohort. At least in pts treated with standard-induction therapy, MEL200 should be considered the standard conditioning regimen for ASCT eligible MM pts.
Brioli:Janssen: Honoraria; Celgene: Honoraria, Other: Travel support, Research Funding. Mügge:Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding. Scholl:Abbivie: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support; MDS: Other: Travel support; Carreras Foundation: Research Funding. Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Sayer:RIEMSER Pharma GmbH: Honoraria. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding. von Lilienfeld-Toal:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria, Other: Travel support, Research Funding.
Abstract To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic ...stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.
Background
Activating mutations of the receptor tyrosine kinase FLT3 (fms-related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, ...FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy.
Patients and methods
We retrospectively analyzed the response to induction chemotherapy and the outcome of 76 patients with FLT3-ITD-positive AML including 50 patients who underwent allogeneic SCT. Furthermore, efficacy of TKI treatment was evaluated in 18 patients (median age 54 years, range 21–74) with relapsed or refractory FLT3-ITD-positive AML.
Results
Response to induction chemotherapy in 76 FLT3-ITD-positive AML patients was characterized by a complete remission (CR) rate of 68%. In total, 50 of 76 patients (66%) underwent allogeneic SCT including 40 patients (80%) in CR. Relapse of AML was observed in 21 of 47 patients (45%) after allogeneic SCT with a median relapse-free survival (RFS) of 13 months (range 3–224) for patients with CR prior to or at day +30 after SCT. Myeloablative conditioning resulted in an improved median RFS of 29 months (4–217) as compared to a reduced intensity conditioning protocol prior to allogeneic SCT with a RFS of 8 months (1–197,
P
= 0.048), respectively. Median OS of FLT3-ITD-positive AML was 17 months (5–225) for patients who received an allogeneic SCT as compared to 9 months (1–184) for patients who did not undergo SCT. Response of FLT3-ITD-positive AML to sorafenib was characterized by only 3 of 18 patients achieving a bone marrow response (17%), while there was no response to second-line treatment with ponatinib.
Conclusion
This “real-life” data reflect the continuing challenge of FLT3-ITD-positive AML and confirm the poor outcome even after allogeneic SCT. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML is still limited and requires substantial improvement, e.g., by the introduction of second-generation inhibitors targeting constitutively active FLT3.
Purpose
Allogeneic hematopoietic stem-cell transplantation (alloHSCT) is physically and psychosocially demanding. Among transplant recipients, adolescent and young adults (AYA) represent a special ...group, as disease occurs early in life, resulting in the prospect of long survival time and high burden of alloHSCT sequelae. However, data focusing on AYA undergoing alloHSCT are rare.
Methods
Data resulting from a prospective multicenter trial initially focusing on graft-versus-host disease (GvHD) after alloHSCT were reused to analyse the differences between AYA and elderly patients. In total, data of 205 alloHSCT recipients were evaluated. Patients completed the FACT-BMT, HAP, SF-36, 24-AM, LOT-R, BSSS, HADS, and GvHD questionnaires.
Results
Median age of AYA and non-AYA patients was 29 and 52 years. Using 24-AM-Test, evaluating personality traits, non-AYA reported to be more conscientious (
p
= 0.033). However, AYA described higher quality of life regarding physical role functioning (
p
= 0.001), physical functioning (
p
= 0.002), bodily pain (
p
= 0.023), and emotional role function (
p
= 0.027) in the SF-36. General health perception, vitality, social role functioning, and mental health were comparable among both groups. On HAP scale, AYA reported higher maximum (
p
= 0.003) and adjusted activity scores (
p
= 0.002), but showed similar restrictions regarding activity, self-supply, and self-determination.
Conclusion
AYA represent a particular group characterized by higher physical well-being and activity scores, and significantly vary from non-AYA patients in psychosocial aspects. Studies covering distinctive features of AYA undergoing alloHSCT are warranted to improve awareness of the special needs of this group.
Introduction. Several alternative donor sources are currently available for patients who lack an HLA-matched related or unrelated donor, including haploidentical, cord blood and one antigen ...HLA-mismatched donors (9/10 mMUD). Use of post-transplant (allo-HSCT) cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis allowed outcome improvements in the haploidentical setting. Its use has also been reported as a safe and feasible option in 9/10 mMUD transplants. However, to date, the main strategy used as GVHD prophylaxis in 9/10 mMUD allo-HSCT is in vivo T-cell depletion with antithymocite globulin (ATG). Data comparing these two different anti GVHD prophylaxis strategies in 9/10 mMUD allo-HSCT are limited.
Methods. We compared PTCY versus ATG as GVHD prophylaxis in patients undergoing 9/10 mMUD allo-HSCT for which high-resolution HLA-allele typing was available in the ALWP/EBMT data registry. Included were adult patients (age>18 years) undergoing their first allo-HSCT for acute myeloid leukemia (AML) during the period 2007-2017. All disease status were allowed. Propensity score matching was performed to reduce and eliminate confounding effects. Each patient receiving PTCY was matched with two patients receiving ATG using the nearest neighbor or exact matching. Variables included in the propensity score model were: disease status at time of allo-HSCT, conditioning regimen, age, secondary AML, female donor to male recipient, source of stem cells, patient and donor CMV serology status.
Results. Globally, 93 patients receiving PTCY were identified and matched with 179 patients receiving ATG. Secondary AML was reported in 20% and 18% of patients in ATG and PTCY groups, respectively. Most patients were in first complete remission at time of allo-HSCT (55% and 56% in PTCY and ATG group, respectively), while nearly 29% of patients in both groups underwent allo-HSCT with active disease. Ciclosporine (csA) and mycophenolate mofetil (MMF) were the systemic immunosuppressive agents more frequently associated to either PTCY (42%) or ATG (49%). Other well represented associated immunosuppressive agents were tacrolimus and MMF in ATG group (20%), followed by 14% of patients receiving csA alone with ATG. In PTCY group, 39% of patients received csA and methotrexate as associated immunosuppressive agents. Conditioning regimen was myeloablative in 50% of patients in both groups. Peripheral blood was the preferred stem cell source (91% in both groups). Among the variables not included in the propensity score model, some differences were observed between the two groups. Median follow-up was longer in the ATG group (27.4 versus 14.2 months, p<0.01). Gender was more frequently male in PTCY group (60% versus 45%, p<0.02). Median year of allo-HSCT was 2014 and 2015 in ATG and PTCY groups, respectively (p<0.01). Similar engraftment rates were observed for both groups (95% and 96% in PTCY and ATG groups, respectively). At 2 years, leukemia-free survival (LFS) was higher in patients receiving PTCY (55% vs 35%, p<0.05), severe (grade III-IV) acute GVHD was lower (9% vs 19%, p<0.04) and GRFS higher (37% vs 21%, p<0.02) as compared to patients receiving ATG, while no differences were observed in relapse incidence (RI)( 29% vs 37%, p=0.31), overall survival (OS, 56% vs 38%, p=0.06) and in non-relapse mortality (NRM) (16% vs 29%, p=0.06). Main causes of death were similarly distributed in both groups, with infectious complications being more frequently represented (25% and 22% in the PTCY and ATG groups, respectively). Grade II-IV acute GVHD (30% vs 32%, p=0.39) and chronic GVHD (39% vs 36%, p=0.35) were also similar in the two groups.
Conclusions. In patients undergoing 9/10 mMUD allo-HSCT, use of PTCY as GVHD prophylaxis is a safe and feasible option, representing a possible valid and superior alternative to ATG. Use of PTCY, indeed, may ensure a lower incidence of severe acute GVHD and higher LFS and GRFS as compared to ATG. These registry based results may serve the basis for a prospective randomized trial comparing PTCY to ATG as anti GVHD prophylaxis in 9/10 mMUD allo-HSCT.
Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Mohty:MaaT Pharma: Consultancy, Honoraria.
Chronic graft-versus-host disease (cGVHD) associated morbidity and mortality remain major barriers for successful allogeneic hematopoietic stem cell transplantation (alloHSCT). Currently, no reliable ...measures are established to monitor cGVHD activity changes for use in clinical trials. The Human Activity Profile (HAP) patient self-report was proposed by the National Institutes of Health (NIH) cGVHD consensus project as an independent measure of patients' functional status that could also indirectly reflect improvement of cGVHD, but that has not been validated in an alloHSCT patient population. One hundred seventy-six patients (median age 44 years range: 18-72 years after alloHSCT were evaluated with a German translation of the HAP, the NIH criteria-based cGVHD activity assessment, the Lee cGVHD Symptom-Scale, FACT-BMT, SF36, Berlin Social Support Scale, 24-Item Adjective Measure (24-AM), Hospital Anxiety and Depression Scale, and the NCCN-Distress-Thermometer. Enrollment occurred a median of 286 (range: 85-4003) days after alloHSCT. Follow-up surveys were conducted at 1, 2, 3, 5, 8, and 12 months after the baseline survey. Although 117 patient had cGVHD at time of enrollment (mild n = 33, moderate n = 50, or severe n = 34), 59 patients were included into the study in the absence of cGVHD between days 85 and 395 after transplantation. The maximum activity score (MAS) and adjusted activity score (AAS) of the HAP correlated inversely with grading of cGVHD severity (mild, moderate, or severe) (r = −0.25 for MAS and −0.24 for AAS). Lung manifestations of cGVHD correlated with AAS (r = 0.17), but not with MAS. HAP scores correlated with subscales from other instruments measuring physical domains, especially the physical functioning scale of the SF36. Performance was improved by use of an HSCT-modified HAP scoring system that excluded activities prohibited within the first year after alloHSCT. No significant correlation of the HAP was found with personality, age, sex, symptom burden, or social functioning or social well-being. Moreover, the HAP displayed a higher sensitivity to change of cGVHD activity compared to the SF36 and the FACT-BMT. In addition, steroid myopathy correlated with both HAP scores, but not the SF36. The HAP is a simple and valid questionnaire for the evaluation of the physical activity in patients after alloHSCT, with the advantage of detecting changes in cGVHD status independently of other quality-of-life measures and with a superior sensitivity compared to the SF36.
Over 3000 persons undergo allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in Germany every year. Advances in allo-HSCT have prolonged the survival of treated patients but have ...concomitantly increased the risk of long-term complications that impair their quality of life.
This literature review of the long-term sequelae of allo-HSCT is based on pertinent articles that were retrieved by a selective search of PubMed, and on current international guidelines. Case reports were excluded from consideration.
Hardly any randomized clinical trials have been performed to investigate the long-term outcome of allo-HSCT, but international consensus-based guidelines have been published. 50% to 70% of patients treated with allo-HSCT develop chronic graft-versus-host disease (cGVHD) within ten years of treatment. Transplant recipients are at higher risk of infection, including the reactivation of dormant herpes viruses; therefore, vaccination is recommended, as described in the current guidelines. Gonadal dysfunction arises in up to 92% of men and up to 99% of women; its frequency depends on the timing of transplantation, on radiotherapy, and on other factors. The medications that transplant recipients need to take can impair liver function, and transfusionassociated hemosiderosis can do so as well. 40% to 50% of patients suffer from lipid metabolic disturbances that increase the risk of myocardial infarction, peripheral arterial occlusive disease, and stroke. Their life expectancy is shorter than that of the overall population.
Measures should be taken to prevent the potential long-term complications of allo-HSCT. All patients who have been treated with allo-HSCT should receive individualized, risk-adapted, and multidisciplinary follow-up care, so that any complications that arise can be correctly diagnosed and appropriately treated. Long-term follow-up care could be improved by prospective clinical trials investigating the long-term sequelae of allo-HSCT, as well as by consistent, uniform documentation of these sequelae in supraregional data registries.
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