Poor Risk Myelodysplastic Syndrome Research Articles

TP53 Mutations Are Associated with Increased Infections and Reduced Hematopoietic Cell Transplantation Rates in Myelodysplastic Syndrome and Acute Myeloid Leukemia

Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n=352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P=.028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P=.005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.

A Phase 1/1b Multicenter Ascending Dose Study to Evaluate the Safety of HA-1 Minor Histocompatibility Antigen-Reactive TCR-Modified T Cells (BSB-1001) in Patients Undergoing HLA-Matched Allogenic Hematopoietic Stem Cell Transplant (alloSCT) for MRD+ AML or ALL or Poor/Very Poor Risk MDS

Background: AlloSCT can cure patients with acute leukemia and high-risk myelodysplastic syndromes (MDS). However, post-transplant relapse remains the greatest single cause of post-transplant death, occurring in up to 80% of high-risk patients. In HLA-matched alloSCT, alloreactive donor T cells target minor histocompatibility antigens (miHAs), which are peptide products of coding polymorphisms that distinguish recipients from donors. These alloreactive T cells can target leukemic cells, mediating the graft-vs-leukemia (GVL) effect; unfortunately, they also can cause graft-vs-host disease (GVHD). Pre-clinical mouse models (Blood, 2011) demonstrate that CD8+ T cells that target miHAs with expression limited to hematopoietic cells can mediate GVL without causing GVHD. To translate this concept for how to safely augment GVL to the clinic, BlueSphere Bio (BSB) used its high throughput T cell receptor (TCR) discovery and characterization platforms to clone a panel of TCRs reactive against the HLA-A*02-restricted miHA, HA-1, which is expressed mostly in hematopoietic cells. These receptors were cloned from a multiparous A*02:01 HA-1- woman who was immunized to HA-1 through pregnancy. A high affinity TCR specific for HA-1 and not reactive against allogeneic HLA molecules was chosen to create a cellular therapeutic designed to mediate GVL and enhance donor engraftment with a lower risk for GVHD, relative to polyclonal donor T cells. The anti-HA-1 T cell product (BSB-1001) is composed of donor CD8+ T cells transduced with a lentivirus vector encoding the anti-HA-1 TCR and the RQR8 tag, which expresses an epitope from CD20, thereby enabling the in vivo killing of BSB-1001 cells with rituximab. CRISPR-cas9 editing of the CD8+ T cells deletes the endogenous TCRα and β chains with >95% efficiency. This increases expression of the TCR and reduces risk of GVHD caused by native TCRs, as well as possible off-target reactivities generated by pairing of endogenous and introduced TCR chains. BSB-1001 cells specifically kill HLA-A*02:01, HA-1+ targets, with no activity against cells that are HLA-A*02:01+ but HA-1-, or cells that are HA-1+ but are HLA-A*02:01-. BSB-1001 is also not reactive against a panel of B lymphoblastic cell lines (LCL) expressing allogeneic HLA molecules. Importantly, efficient target killing is seen at effector:target ratios as low as 0.1, and maintained after several rounds of ex-vivo expansion following target cell challenge, a likely predictor of potency and persistence in vivo. Study Design: The first in human Phase 1/1b study is a multicenter, open-label, single dose study with a 3+3 ascending design with the option to expand accrual at a promising dose. Subjects must have ALL, AML or high-risk MDS with evidence of disease after the last therapy, be HLA-A*02:01 HA-1+ and have a 10/10 HLA-matched HA-1- related or unrelated donor. GCSF-mobilized donors will undergo leukapheresis. From this product, a small fraction of cells will be removed for BSB-1001 manufacturing; the remainder will undergo CD34-selection and cryopreservation until SCT. After BSB-1001 manufacturing is complete, patients will undergo ablative conditioning (choice of three regimens), followed by infusion of the CD34-selected cells and then BSB-1001. Patients will not receive anti-T cell antibodies and will receive no prophylactic pharmacologic immunosuppression. Subjects must otherwise be suitable for ablative conditioning using standard criteria. The primary objective is to establish a recommended dose of BSB-1001 based on its dose-limiting toxicities and the magnitude of post-infusion BSB-1001 expansion. The primary endpoint is determining the incidence of treatment-emergent adverse events, including dose-limiting toxicities. Additional endpoints include rates of engraftment, incidences of cytokine release syndrome (CRS) and acute and chronic GVHD, quantitation of malignant hematopoiesis and lineage-specific donor chimerism. CRS and GVHD, should they occur, will be treated per institutional standards. Rituximab can be administered to kill BSB-1001 cells in case of refractory CRS or GVHD. Enrollment is anticipated to begin in 1Q2023. BSB is also developing panels of TCRs targeting additional relatively hematopoietically-restricted miHAs with prioritization based on the frequencies of the restricting HLAs and the immunogenic/nonimmunogenic miHA alleles.

The CXCL12/CXCR4 Pathway As a Potential Target of Tipifarnib in Acute Myeloid Leukemia and Myelodysplastic Syndromes

BackgroundCXCL12 is a chemokine that is essential for homing of myeloid cells in the bone marrow (BM). It has been postulated that a CXCL12 receptor present in myeloid cells, CXCR4, signals in part through HRAS, a protein that is uniquely dependent on farnesylation for activity. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT) that had been shown to provide clinical benefit in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, no molecular target that could explain the activity of tipifarnib in AML and MDS has been identified. Based on initial observations in T cell lymphoma (Witzig EHA 2017), we investigated a role for CXCL12 and myeloid cell homing in BM as biomarkers of the activity of tipifarnib in AML and MDS studies.MethodsCTEP20 was a phase 2, multicenter, open-label study that investigated the efficacy and safety of tipifarnib in 158 older adults with previously untreated, poor-risk AML. AML301 was a phase 3 (N=457), multicenter, open-label study that evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients with newly diagnosed, de novo, or secondary AML. INT28 was a multicenter phase 2 study that evaluated tipifarnib in 82 pts with poor-risk MDS. Global gene expression data generated using the Affymetrix U133A gene chip from 34 pretreatment BM samples collected from CTEP20 pts (GSE8970) was analyzed with respect to pretreatment hematological parameters and study outcomes. The Kaplan-Meier method was employed to estimate survival and progression free survival (PFS) and the analysis of prognostic variables. Clinical trial information: NCT00027872, NCT00093990, NCT00050154.ResultsNine complete responses (CR) and 13 best responses of progression of disease (PD) were observed in 34 pts with available BM gene expression data in study CTEP20. Pts in the 3rd (upper) tertile of CXCL12 expression experienced 6 CRs and 2 PDs whereas 1 CR and 8 PDs were observed in the 1st (lower) tertile (p=0.015). BM homing of AML blasts correlated with CXCL12 expression: Median percentage of BM blasts (BMB) and peripheral blasts (PB) were, respectively, 45% and 0% in the upper CXCL12 tertile, and 30% and 26.5% in the lower tertile (p<0.001) (Figure, A). Pts with high tumor burden in BM (BMB blasts>40%) and low circulating blasts (PB<1%) (N=5) had high CXCL12 expression in BM (3423 vs 742 counts, P<0.001, N=27) and experienced prolonged clinical benefit, with 5 CRs and a median PFS of 431 days (431 vs 35 days, HR=0.23, P<0.001, N=27) (Figure, B). The effect of BM homing was then investigated in the phase 3 AML301 trial of tipifarnib vs BSC. While the overall study (N=457) failed to identify an increased efficacy of tipifarnib compared with BSC (median survival of 109 vs 107 days, hazards ratio, HR=1.02, ns), median survival approximately doubled in the tipifarnib am compared with BSC in the subset of patients with high BMB (>40%) and low PB (<10%) while no effect was observed in the control arm (201 vs 109 days, HR=0.58, p=0.02, N=82) (Figure, B). Since CXCL12 is also a potent chemotactic factor for normal neutrophils and syndromes of hyperactivation of the CXCL12/CXCR4 pathway present with neutropenia, we investigated whether neutropenia could be a surrogate of tipifarnib activity. In AML301 pts with WBC counts>LLN (no myelosuppression), increasing neutropenia correlated with increasing clinical benefit from tipifarnib that was due in part to a poorer prognosis of BSC in neutropenic pts (113 vs 80 days median OS, HR=0.81, p=0.036, N=109, for pts with baseline neutrophils<1 giga/L). Finally, we tested the effect of neutropenia on the activity of tipifarnib in INT28. Sixty seven of the 82 MDS pts were transfusion dependent (TD) at study entry. Overall conversion to transfusion independence (TI) and response rate (ORR: CR, CRp, PR) were respectively 16% and 7.5% in the TD pts. Pts with >1 giga/L neutrophils at study entry experienced 5% TI and no responses (N=37) while 30% TI, 2 CRs, 2 CRp and 1 PR were observed in the subset of neutropenic pts.ConclusionCXCL12 expression and BM homing constitute potential biomarkers of the activity of tipifarnib in AML and MDS supporting the hypothesis that the CXCL12 pathway is a potential target of FT inhibitors. [Display omitted] DisclosuresGualberto:Kura Oncology: Employment, Equity Ownership, Other: Chief Medical Officer, Patents & Royalties. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Janes:Wellspring Biosciences: Employment. Kessler:Kura Oncology: Employment. Raza:Kura Oncology: Research Funding; Syros Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Celgene Inc.: Research Funding; Genoptix: Speakers Bureau; Onconova Therapeutics: Research Funding, Speakers Bureau; Janssen R&D: Research Funding.

Comparison of Peripheral Blood and Bone Marrow Molecular Profiling in Primary Myelodysplastic Syndromes (MDS)

AMM and MA – Joint first authorsDiagnosis of myelodysplastic syndromes (MDS) relies on demonstrating peripheral blood (PB) / bone marrow (BM) dysplasia and cytogenetic abnormalities, forming the backbone of the revised International Prognostic Scoring System (IPSS-R). However, assessment of dysplasia is operator dependent and metaphase cytogenetic analysis (MC) is often normal or uninformative creating diagnostic challenges, particularly in patients with early or low risk MDS. Impressive advances have taken place in the last decade in the identification and chronicling of the genetic lesions leading to phenotypic diversity of MDS. We sought to evaluate the value of single nucleotide polymorphism array (SNP-A) based cytogenetic assessment and high throughput sequencing of the 24 genes most frequently mutated in MDS to determine if genetic abnormalities in the BM are reflected in the PB thus enabling easy assessment of response to treatment and/or disease progression.A MiSeq based gene panel comprising of 24 frequently mutated MDS genes: ASXL1, CBL, CEBPA, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, KDM6, KIT, KRAS, NPM1, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, ZRSR2 and CytoHD/750K SNP-A karyotyping was applied to both PB and BM concurrent samples. Genomic aberrations and non-synonymous variant calls were filtered using public databases to exclude polymorphisms.PB and BM from 201 MDS patients [median 62 years (17-88)] followed up for median 21 months (0.3-171) was analysed. Sixty (30%) patients received supportive care only whilst others were treated with MDS/AML directed therapies. The WHO subtypes were: 5q- syndrome (n=26), refractory cytopenia/s (RA/RCMD, n=53), refractory anaemia with excess blasts/acute myeloid leukaemia (RAEB/AML, n=51), refractory anaemia with ringed sideroblasts (RARS/RCMD-RS, n=20) and other subtypes (including myeloproliferative and hypoplastic MDS, n=51). Based on the IPSS-R risk groups 62% had low risk disease: classified as very low (n=35), low (n=89), intermediate (n=42), high (n=16) and very high (n=19) risk groups. Metaphase cytogenetic analysis was normal (NK-MC) in 113(56%), abnormal (AK-MC) in 65(32%) patients and in 23(12%) MC failed. SNP-A was informative in all patients identifying a normal (NK-SNP) in 93(46%) and abnormal (AK-SNP) in 108(54%) patients, respectively. A comparison of BM and PB by SNP-A, showed 190 patients having an identical karyotype (95% concordance). BM SNP-A identified 36 (32%) patients with SNP-A abnormalities not detected by MC, changing the IPSS-R in 49 (24%) patients overall. Inclusion of SNP-A abnormalities changed the IPSS-R risk group in 28 (25%) of NK-MC patients; from good to intermediate (n=21), poor (n=5) and very poor (n=2) groups, respectively. In 9/11 patients with discordant SNP-A karyotypes between BM and PB, the IPSS-R remained unchanged. We found no difference in the clonal burden between PB and BM for gains and CN-LOH. However, for deletions, the clonal size was significantly lower in BM [median 1.4 (1 – 1.9)], than PB [median 1.5 (1 – 1.95), p<0.001].Mutational profiling from 183 patients revealed 248 and 240 mutations in BM and PB, respectively. BM and PB mutation profiles were identical in 171 patients (93% concordance) (Fig 1). In 11/12 patients with discordant mutation profiles, additional identical mutations and SNP-A abnormalities were noted in both BM and PB. Similarly, clone size was lower (p= 0.53) in the PB [median 27%, (1%-96%)] compared to BM [median 30%, (1%-100%)] and, in addition, there was no difference in the overall number or the type of mutation between the BM and PB. Interestingly, analysis of known poor risk MDS gene mutations (ASXL1, EZH2, RUNX1, P53 and U2AF1) identified 85 mutations in BM compared to 80 in the PB. In 5 patients where these mutations were discordant, additional identical mutations were detected in both BM and PB. Patients with ASXL1 and TP53 mutations had significantly lower clonal burden in PB (p<0.001) compared to BM in contrast to RUNX1 and EZH2 where there was no difference in the clone size. Using PB we were able to show that both SNP-A defects and gene mutations were efficiently detected when compared with BM.This study confirms that PB can reliably substitute for BM for all molecular assays in MDS; which is highly relevant for the clinical assessment of this relatively elderly group of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Targeting the Pro-Survival Protein c-MET With ARQ 197 Inhibits Growth of Multiple Myeloma Cells

Background: Erythroleukemia is a rare form of acute leukemia often accompanied by unfavorable cytogenetics. Traditionally treated with a standard cytarabineebased induction regimen, median survival is poor (w8 months). Hypomethylating drugs had demonstrated clinical activity in patients with poor risk myelodysplastic syndromes (MDS) with improved overall survival compared to best supportive care. Methods: Retrospective review from 33 patients with erythroleukemia treated with either hypomethylating agents (at three different institutions: MD Anderson Cancer Center, Moffitt Cancer Center and Roswell Park Cancer Institute since November 2002) and comparison with standard of care. Results: The median age was 67 years (range, 38-84), 9 (27%) were females. Treatment was with azacytidine (AZA) in 12 (36%) and with decitabine (DAC) in 9 (27%) of the cases. 12 patients received therapy with cytarabine-based chemotherapy agents as induction. Cytogenetic analysis included diploid in 9, complex abnormalities in 19 and intermediate risk in 5. FLT3 mutations were absent in all 16 patients tested. Fourteen (67%) of the 21 patients treated with hypomethylating agents achieved a complete remission whereas five (42%) patients treated with induction chemotherapy. This was accompanied by complete cytogenetic remission in 14 of 16 evaluable patients in the hypomethylating group. After a median follow up of 8 months (range,1-58) the median overall survival time was 15.4 months (95%CI: 7.1 to 24.8) in those who receive hypomethylating agents versus 10 months (95%CI: 1.6 to 15.4) in those who did not (P¼0.0322). Conclusion: These results suggest that hypomethylating agents are highly active in patients with acute erythroleukemia and may extend survival compared to standard induction chemotherapy regimens. Benefit from high intensity therapy is limited, suggesting biological overlap with MDS.

Prospective Phase II Multicenter Study of Conditioning with Treosulfan, Fludarabine and Low-Dose (2 Gy) Total Body Irradiation Followed by Hematopoietic Cell Transplantation From Related or Unrelated Donors for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

AbstractAbstract ▪963▪This icon denotes a clinically relevant abstract Background:We showed previously that a transplant conditioning regimen of treosulfan combined with fludarabine was associated with low non-relapse mortality (NRM) and a high probability of survival in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with low or intermediate risk cytogenetics (Nemecek et al, BBMT 2011). Relapse rates were high, however, in patients with high-risk cytogenetics, which resulted in a 2-year relapse-free survival of 39% in this group. Objective:The objective of the present study was to reduce the relapse incidence and improve overall survival (OS) in patients with high-risk AML or MDS by adding low-dose TBI (2 Gy) to the treosulfan plus fludarabine regimen. Patients and methods:Ninety-six patients with AML (n=60) or MDS (n=36) were enrolled. Patients were 60 years of age or younger (median age: 50 years) and had high-risk MDS, unfavorable or intermediate-risk AML in first complete remission (CR) or any AML beyond first CR. Cytogenetic risk in AML was stratified using the Southwest Oncology Group criteria, while the World Health Organization-based Prognostic Scoring System was used in patients with MDS. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days -6 to -4, IV fludarabine 30 mg/m2/day on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of marrow (n=11) or peripheral blood stem cells (n=85) from related (n=27) or unrelated (n=69) donors. Donors were single HLA allele-level mismatched in 9 patients and HLA-matched at the allele level in 87 patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (10 mg/m2 on days +1, +3, +6 and +11 post-HCT) and tacrolimus (days –1 to +180). Results:All evaluable patients engrafted. With a median follow-up of 12.8 (range, 0.2 – 34.7) months in surviving patients, the estimated 2-year progression-free survival and OS were 59% and 68%, respectively. The cumulative incidences of relapse or progression and NRM at 2 years were 30% and 11%, respectively (Figure 1). The incidences of grade II (grades III-IV) acute and extensive chronic GVHD at 2 years were 48% (11%) and 40%, respectively.Relapse occurred in 39% of patients with AML and 18% of patients with MDS (Figure 2A). OS was 61% among patients with AML and 79% in patients with MDS (Figure 2B). In univariate analyses, cytogenetic risk status did not impact relapse for the entire cohort nor for patients with AML or MDS analyzed separately (Figures 3A and 3B). As a result, 2-year OS rates were similar in patients with favorable/intermediate and unfavorable cytogenetic risk AML (64% and 57%, respectively) or in good/intermediate and poor risk MDS (88% and 71%, respectively). Patients with AML with minimal residual disease (MRD; n=10) or in refractory relapse (n=4) at the time of HCT, had higher relapse rates (87% vs. 25%) and lower OS (25% vs. 81%) at 2 years than patients in remission without MRD at the time of HCT. Conclusions:In summary, treosulfan, in combination with fludarabine and low-dose TBI was an effective conditioning regimen for allogeneic HCT in patients with AML (in CR at the time of HCT) or MDS. Relapse and OS rates in patients with high-risk cytogenetics did not differ significantly from those in patients with low or intermediate risk karyotypes. The relapse rate was particularly low in patients with MDS, including those with high risk cytogenetics, and further trials with treosulfan-based regimens are warranted. For patients with AML who have residual disease at HCT novel regimens need to be developed. The data suggest that in patients with AML high risk as defined by cytogenetics had a different impact on outcome than high risk as defined by other parameters, such as tumor burden. [Display omitted] [Display omitted] [Display omitted] Disclosures:Gyurkocza:medac GmbH, Hamburg, Germany: Research Funding. Off Label Use: Off-label usage of treosulfan, fludarabine, methotrexate and tacrolimus will be discussed. Sickle:medac GmbH, Hamburg, Germany: Research Funding. Baumgart:medac GmbH, Hamburg, Germany: Employment. Deeg:medac GmbH, Hamburg, Germany: Research Funding.

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid

5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100 mg/m2, 5 days) plus valproate (VPA; continuous dosing, trough serum level 80–110 μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34+ peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials.

Allogeneic Transplantation with a Treosulfan-Fludarabine Conditioning Regimen Is Feasible and Effective in Elderly Patients with Refractory or Relapsed Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS); Preliminary Results From a Single Center Experience.

Abstract 4318 Backgroundthe majority of AML and poor risk MDS cases in the elderly (>60 years) are resistant to induction chemotherapy or relapse after initial response; thereafter, most of these patients (pts) receive only supportive treatments, with an expected survival of few weeks. Allogeneic (allo) stem cell transplantation (SCT) could be the only potentially salvage strategy; actually, for the high probability of letal toxicites due to the conditioning regimen, acute graft-versus-host disease (aGvHD) and infections, these pts are rarely offered this procedure.Since 2005, we have transplanted 12 pts, age>60, with refractory or relapsed AML/MDS, from an allogeneic donor. Data on feasibility and outcome are here reported. Aimto retrospectively evaluate data on alloSCT in elderly pts with refractory or relapsed AML and MDS, transplanted at our Institute. Patients and Methodsperiod 9/2005 to 4/2009, 12 pts, median age 65 (61-72). Performance status (Karnofsky): median 90% (80-100), HCT-CI: median score 1 (0-4). Diagnosis (WHO): AML 3, AMLMD 4, RAEB2 2, MDS/MPD 2, therapy-related AML 1. Median number of chemo cycles before SCT: 2 (1-7), all pts received at least 1 cycle with intermediate or high-dose cytarabine, 2 pts also received an autologous SCT. Donors: matched sibling 2, matched unrelated 2, related haploidentical 7, cord blood 1. Disease status at SCT: primary refractory 7, relapsed 5. Conditioning regimen: treosulfan (TREO) 14 g/sqm for 3 days, fludarabine (FLU) 30 mg/sqm for 5 days, ATG 10 mg/kg for 3 days for SCT from alternative donors. GvHD prophylaxis: T-cell depletion in 2 cases, cyclosporine (CSA)/methotrexate in 7, rapamycin/mycophenolate mofetil (MMF) in 3. Results11/12 (92%) pts engrafted and were in CR at day +30, with 95-100% donor chimerism (VNTR). Deaths within day 30 and day 100 were 0 and 3 (25%), respectively. Acute GvHD: 6 pts (55%), grade II (3) or III (3), only of skin in 3 cases, skin+liver in 1, only intestinal in 2. Relapses were 4 (36%). Overall TRM was 25% (3 pts), with all deaths due to infections during immunosuppression for aGVHD; 5 more pts died because of disease progression. Median OS from SCT of all 12 pts was 180 (56-1150) days, DFS (11 pts) was 128 (24-1114) days. At last follow-up (FU) 4 pts (33%) are alive, all in CR with a median FU of 406 (128-1150) days. ConclusionsalloSCT proved to be feasible in our elderly pts with AML/MDS refractory to induction or relapsed after initial complete remission. Early letal toxicities, due to the conditioning treatment, were absent; aGVHD, infections and relapses were the principal causes of mortality. Up to now, prolonged survival (>1 year) free from disease has been obtained in 25% of pts; of the 4 pts alive in CR, only 1 is receiving immunosuppression (CSA), for chronic GVHD. In conclusion, the TREO-FLU association showed a reduced-toxicity profile in these frail pts and a substantial anti-leukemic effect. Better prevention of aGVHD should be obtained, expecially after SCT from alternative donors, possibly with the rapamycin/MMF combination, which we are currently investigating at our Institute. AlloSCT after TREO-FLU conditioning can be considered an effective option for AML/MDS elderly pts with active disease after failure of previous intensive treatments. Disclosures:bonini:MolMed S.p.A.: Consultancy.

Treatment of Poor Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia with a Combination of 5-Azacytidine and Valproic Acid

The DNA demethylating agent 5-Azacytidine (5-Aza) is the first drug to achieve a survival benefit in patients with poor-risk MDS. In vitro, synergism with inhibitors of histone deacetylases has been described, and the clinical feasibility of combining 5-Aza with Valproic Acid (VPA) has also been demonstrated. Response rates are at least comparable to 5-Aza monotherapy and time to response appears to be significantly shortened. However, the optimal dosing schedule for this combination is still uncertain.VPA was administered orally and continuously to achieve a serum level of 80–110μg/ml. 5-Aza was given at an increased dosage of 100mg/m2/d in a 5-day schedule every 28 days, in order to avoid weekend applications. Between March and Juli, 2007, 25 patients were included; 24 received at least one complete cycle of therapy. Median age was 73 (59–87) years. Diagnoses were 7 RAEB, 3 RAEB-T, 11 AML, 3 CMML (according to FAB), or 1 RAEB I, 4 RAEB II, 6 de-novo AML, 7 secondary AML/MDS, 3 therapy-related MDS/AML, 3 CMML II (according to WHO). All MDS patients had an IPSS score of intermediate II or high. 8 patients showed a normal karyotype, 6 had intermediate-risk single aberrations and 10 had poor-risk cytogenetics. 7 patients had previously received intensive chemotherapy. Karyotype was determined by conventional cytogenetics as well as FISH analysis of circulating 34+-cells and bone marrow.Patients received a median of 5 (1–17) cycles. The response rate was 33%, including 1 CR, 1 CRi, 5 PR and one patient with hematologic improvement but 6% remaining marrow blasts. 9 patients (38%) achieved at least stable disease, 5 of these obtained marrow CR (n=3) or PR (n=2). These patients typically showed a hypoplastic marrow with significantly reduced blast cells but without regeneration of peripheral cell counts. Response rate was highest in previously untreated patients with 10–30% marrow blasts (55%), while only one of 6 patients with relapsed/refractory AML achieved CRi. Cytogenetic remissions occurred in 6 patients (4 cytogenetic CR and 2 PR). Out of 7 patients with chromosome 7 abnormalities, 4 (57 %) responded. Median number of cycles to achieve a response was 2. While it took only 1 or 2 cycles in 5 patients, three patients needed 8 or 9 cycles. Median response duration was not reached, since only 3 patients relapsed after 5, 6, and 10 treatment cycles. Median survival from start of therapy was 8 (1–17) months (see fig.). 6 patients currently remain on treatment.Most patients had transient CNS side effects leading to dose reduction or transient discontinuation in 8 and cessation of therapy in 2. In one patient Coombs-negative hemolysis occurred. It is unknown whether this AE was related to the study drugs. Two patients developed a rash after 5-Aza. Myelosuppression occurred in all patients especially during the initial cycles. Treatment had to be delayed in most of the patients during the first cycles, and dose reductions of 5-Aza were necessary in 7 cases. One patient died of pneumonia after the first cycle. Myelosuppression appeared to be more severe than with 5-Aza alone. Whether this was due to dose intensification of 5-Aza, combination with VPA, or unfavourable patient characteristics remains uncertain.In future studies we would prefer a schedule of 75mg/m2/d for 5 days, which has proven effective in recent trials. Although the combination of demethylating agents and HDAC inhibitors may achieve earlier responses in some patients, this approach does not seem to obviate the need for prolonged treatment. Patients who achieve at least stable disease should be kept on treatment as long as possible. [Display omitted]

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome

AbstractThis multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.

Myeloablative Allogeneic Bone Marrow Transplantation (AlloBMT) with T Cell Depletion (TCD) and Post-Transplant GM-CSF for Patients with High Risk MDS.

Myelodysplastic syndromes (MDS) are a complex and heterogeneous group of hematopoietic stem cell malignancies that are generally incurable outside allo BMT. The toxicities of allo BMT, specifically graft-vs-host disease (GVHD) and end organ toxicity, have limited its use in this traditionally older group of patients (pts) who often have medical co-morbidities. Efforts to apply allo BMT to more pts have focused on reducing the toxicities. Graft manipulation, including TCD, and reduced-intensity conditioning (RIC) regimens have been shown to decrease the upfront mortality of allo BMT; yet improvements in overall survival have been limited due to associated increased post-BMT relapse rates and increased graft failure. Myeloid growth factors have been used commonly, though not systematically, following allo BMT to speed engraftment. Our data, and that of others, suggest that myeloid growth factors may also have anti-tumor properties in MDS by impacting differentiation pathways and/or through their immunomodulatory effects. We developed a clinical trial to determine if the addition of GM-CSF could safely decrease the relapse rate following a TCD allo BMT in pts with high risk MDS. Pts with MDS ≤ 65 undergoing evaluation for a matched sibling allo BMT at the Sidney Kimmel Cancer Center at Johns Hopkins were considered eligible. Pts received a TCD allograft (elutriation and CD34 isolation) following a myeloablative busulfan/cytoxan preparative regimen; GM-CSF @ 250 mcg/m2/day from Day +5 until ANC >2000/m3 × 3 days and then 125mcg/m2/day subcutaneously thru Day +60. A total of 43 pts were treated on the protocol with a median age of 56 (range 30 to 65) yrs. Forty pts had poor risk MDS (cytogenetics and IPSS) and 3 pts had AML upon retrospective pathology review. The addition of GM-CSF was well tolerated post-allo BMT with only 1 pt unable to complete the full dose, planned therapy. The overall survival @ 1 and 3 years was 54% and 50% respectively while the event free survival @ 1 and 3 years was 47% and 33% respectively with median follow-up in the surviving group of 37.5 months. Treatment related toxicity was low with a 9% cumulative incidence of grade III/IV aGVHD and a transplant-related mortality (TRM) of 21% (9/43) with 4 deaths related to GVHD, 4 related to engraftment, and 1 secondary to venoocclusive disease. Cumulative incidence of relapse at data analysis was 40% (17/43) with one patient achieving remission after donor lymphocyte infusion. Engraftment failure was seen in only 9% (4/43) of pts. Taken together, ablative preparative regimens followed by TCD allo BMT can safely be used in older MDS pts with the addition of GM-CSF resulting in acceptable engraftment without increased toxicity. Myeloablative conditioning with TCD and prolonged post-transplant GM-CSF produced favorable results in this group of older, high-risk MDS patients. The role of high dose conditioning for alloBMT for MDS is unclear, but the TRM was similar to the low mortality reported with RIC regimens, and the graft failure and relapse rates may be superior.

Co-Morbidity and Disease Status at the Time of Transplant Predict Outcome Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) for Poor Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML).

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the standard of care in poor risk myeloid malignancies. Identifying factors which predict both non-relapse mortality and relapse risk are imperative to patient selection. We report the outcome of 198 cases of poor risk MDS (n=70) and AML (n=128) who underwent allo-HSCT with either myeloablative (MA) (n=67) or reduced intensity conditioning (RIC) (n=131). A T-cell depleted regimen using Alemtuzumab was administered to all patients receiving RIC and for volunteer unrelated donor (VUD) MA transplants. 13% had a diagnosis of refractory anaemia excess blasts (RAEB I), 14% RAEB II, 15% AML with multi-lineage dysplasia, 49% de-novo AML and 9% chronic myelomonocytic leukaemia. The median age of the RIC cohort was 53years (21–72 years) compared with 31years (17–59 years) in the MA group. On comparison of RIC versus MA cohorts, 31% v 45% had a co-morbidity score of 0, 17% v 25% score 1, 17% v 16% score 2 and 35% v 14% score ≥3 (p=0.025). The Charlson co-morbidity index was used to define the pre-transplant score. No difference in disease status at time of transplant was observed between the RIC and MA groups (p=0.399) with 80% v 71% in first complete remission (CR1), 4% v 6% in second CR (CR2), 2% v 6% partial remission (PR), 9% v 9% progressive disease (PrD) and 5% v 8% dysplastic remission (DysCR). A higher number of VUD transplants 61% versus 45% (p=0.042) were observed in the RIC cohort, whereas a higher proportion of cases with poor risk cytogenetics (42% v 26%) (p=0.01) were observed in the MA group. No difference in FAB classification, prior therapy or HLA disparity was observed between the RIC and MA groups. The median follow-up for the MA and RIC groups was 1782days (50–4300days) and 1014days (168–2211days) respectively. The transplant related mortality (TRM) for the MA and RIC cohorts at day+100 was 31% v 10% and at 3years 47% v 30% respectively. The 3year overall survival (OS) was 41% v 47% (p=0.062), 3year disease free survival (DFS) 36% v 43% (p=0.156) and 3year relapse rate 34% v 40% (p=0.28) for the MA and RIC groups respectively. Multiple cox regression analysis identified co-morbidity risk score (p=0.003) disease status at time of transplant (p=0.012) and cytogenetic risk group (p=0.041) as the most significant factors affecting OS for all allogeneic HSCT. Analysis of factors affecting DFS further identified co-morbidity risk group (p=0.007) disease status at time of transplant (p=0.015) and cytogenetic risk group (p=0.022) as retaining significance. On analysis of RIC and MA cohorts separately co-morbidity and disease status remain the most significant variables affecting OS and DFS. With respect to disease status, PR and PrD consistently demonstrate significantly worse outcome than CR1, CR2, or DysCR subgroups. A co-morbidity index of ≥2 displayed inferior outcome to a score of 0 or 1. Age, sex, HLA disparity or sibling v VUD showed no effect on OS or DFS. In summary, the results demonstrate a trend towards improved OS following RIC transplantation, with no significant difference in DFS. Patient selection for allo-HSCT should not be based on age alone, whereas response to chemotherapy and the use of co-morbidity scores more accurately predict outcome following both MA and RIC regimens.

Successful Use of Haploidentical Stem-Cell Transplantation With KIR Mismatch As Initial Therapy for Poor-Risk Myelodysplastic Syndrome

Successful Use of Haploidentical Stem-Cell Transplantation With KIR Mismatch As Initial Therapy for Poor-Risk Myelodysplastic Syndrome

A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m(2) was escalated by approximately 33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m(2) for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m(2) was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m(2) and 1 with acute myeloid leukemia treated with 600 mg/m(2), achieved complete remission. VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

Low dose Idarubicine, Vincristin, Prednisone, and G-CSF plus ATRA for the treatmant of poor risk myelodysplastic syndrome (MDS)

Low dose Idarubicine, Vincristin, Prednisone, and G-CSF plus ATRA for the treatmant of poor risk myelodysplastic syndrome (MDS)