Association of geriatric measures and global frailty with cognitive decline after allogeneic hematopoietic cell transplantation in older adults.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, and its potential impact on cognition in this population is understudied. This work aims to evaluate the ability of cancer-specific geriatric assessments (cGA) and a global frailty index based on accumulation of deficits identified in the cGA to predict the risk of cognitive decline after alloHCT in older adults. MATERIALS AND METHODS: AlloHCT recipients aged 50 years or older completed a cGA, including a cognitive evaluation by the Blessed Orientation Memory Concentration (BOMC) test, at baseline prior to alloHCT and then at 3, 6, and 12 months after transplant. Baseline frailty was assessed using a deficit accumulation frailty index (DAFI) calculated from the cGA. A multinomial logit model was used to examine the association between predictors (individual cGA measures, DAFI) and the following three outcomes: alive with stable or improved cognition, alive with cognitive decline, and deceased. In post-hoc analyses, analysis of variance was used to compare BOMC scores at baseline, 3, 6, and 12 months across frailty categories. RESULTS: In total, 148 participants were included, with a median age of 62 (range 50-76). At baseline, 12% had cognitive impairment; at one year, 29% of survivors had improved BOMC scores, 33% had stable BOMC, and 37% had worse BOMC. Prior to transplant, 25% were pre-frail and 11% were frail. Individual baseline cGA measures were not associated with cognitive change at one year as assessed by BOMC. Adjusting for age, sex, and education, those who were frail at baseline were 7.4 times as likely to develop cognitive decline at one year than those who were non-frail, although this finding did not reach statistical significance (95% confidence interval [CI] 0.74-73.8, p = 0.09). The probability of being alive with stable/improved cognition at 12 months for the non-frail, pre-frail, and frail groups was 43%, 34%, and 8%, respectively. DISCUSSION: Baseline geriatric measures and frailty were not significantly associated with cognitive change as assessed by BOMC in adults aged 50 or older after alloHCT. However, the study was underpowered to detect clinically meaningful differences, and future work to elucidate potential associations between frailty and cognitive outcomes is warranted.

Patterns and Predictors of Functional Decline after Allogeneic Hematopoietic Cell Transplantation in Older Adults.

As allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, geriatric assessment (GA) has been identified as a useful tool for predicting outcomes, particularly functional status. However, very few studies have examined the longitudinal change in GA measures in the post-alloHCT period. The objectives of this study were to describe the longitudinal change in GA and quality of life (QoL) measures after alloHCT and to identify predictors of greater functional decline post-transplantation. In this single-center prospective cohort study, patients age ≥50 years scheduled for alloHCT completed a cancer-specific GA and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) survey at baseline prior to alloHCT and then at 3, 6, and 12 months post-transplantation. Changes in GA and QoL measures at each post-transplantation time point (3, 6, and 12 months) compared to baseline were analyzed using paired t-tests. Exploration of potential predictors of greater post-transplantation functional decline, as measured by instrumental activities of daily living (IADL) and the Medical Outcomes Study Physical Health scale (MOS-PH), were examined using linear regression and the chi-square 2-sample test of proportions. Mean functional status generally exhibited a pattern of decline at 3 to 6 months post-alloHCT, with recovery to near baseline by 12 months. Mean mental health and emotional QoL were lowest at baseline and improved at all post-transplantation time points. Differences in baseline clinical characteristics were not associated with any differences in functional trajectories. Differences in baseline GA measures-patient-rated Karnofsky Performance Status, IADL, MOS-PH, Timed-Up-and-Go, Blessed Orientation-Memory-Concentration test, and Mental Health Inventory 5-also did not predict greater functional decline at 3 months. Patients whose IADL was improved or maintained at 3 months generally maintained their functional status at 6 and 12 months. Similarly, most patients who had an IADL decline at 3 months still had a functional decline at 6 months, although a proportion did have functional recovery by 12 months. Compared with patients who had improved/maintained IADL at 3 months, those with a decline in IADL at 3 months were significantly more likely to have persistent functional decline at 6 months (P < .0001) and 12 months (P = .02). In older alloHCT recipients, mean functional status declines short term after alloHCT with the possibility of recovery by 6 to 12 months, whereas mean mental and emotional health improve post-alloHCT. Functional decline at 3 months post-alloHCT is associated with persistent functional decline at 12 months.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.

Functional Status as Measured by Geriatric Assessment Predicts Inferior Survival in Older Allogeneic Hematopoietic Cell Transplantation Recipients.

Allogeneic hematopoietic cell transplantation (alloHCT) has been increasingly offered to older adults with hematologic malignancies. However, optimal methods to determine fitness for alloHCT have yet to be defined. We evaluated the ability of a comprehensive geriatric assessment (CGA) to predict post-alloHCT outcomes in a single-center prospective cohort study of patients age 50 years and older. Outcomes included overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM). A total of 148 patients were included, with a median age of 62 years (range, 50 to 76 years). In multivariate regression analysis, several CGA measures of functional status were predictive of post-alloHCT outcomes, after adjusting for traditional prognostic factors. Any deficit in instrumental activities of daily living (IADL) was associated with inferior OS (hazard ratio [HR], 1.81, 95% confidence interval [CI], 1.07 to 3.08; P = .03) and PFS (HR, 1.85; 95% CI, 1.15 to 2.99; P = .01). A Medical Outcomes Study Physical Health scale (MOS-PH) score <85 was associated with inferior OS (HR, 1.96; 95% CI, 1.13 to 3.40; P = .02), PFS (HR, 1.75; 95% CI, 1.07 to 2.88; P = .03), and increased NRM (subdistribution HR, 2.57; 95% CI, 1.12 to 5.92; P = .03). MOS-PH score was also associated with the number of non-hematologic grade ≥3 adverse events within the first 100 days after alloHCT (rate ratio, 1.61; 95% CI, 1.04 to 2.49; P = .03). These findings support previous work suggesting that IADL is an important prognostic tool prior to alloHCT. MOS-PH is newly identified as an additional metric to identify older patients at higher risk of poor post-alloHCT outcomes, including toxicity and NRM.

Histone Deacetylase Inhibition with Panobinostat Combined with Intensive Induction Chemotherapy in Older Patients with Acute Myeloid Leukemia: Phase I Study Results.

PURPOSE: The histone deacetylase (HDAC) inhibitor panobinostat potentiates anthracycline and cytarabine cytotoxicity in acute myeloid leukemia (AML) cells. We hypothesized that panobinostat prior to and during induction chemotherapy would be tolerable and augment response in patients showing increased histone acetylation. PATIENTS AND METHODS: Patients received panobinostat 20-60 mg oral daily on days 1, 3, 5, and 8 with daunorubicin 60 mg/m2/day intravenously on days 3 to 5 and cytarabine 100 mg/m2/day intravenously by continuous infusion on days 3 to 9 ("7+3"). Peripheral blood mononuclear cells (PBMCs) were isolated for HDAC expression and histone acetylation changes. RESULTS: Twenty-five patients ages 60-85 years (median age, 69) were treated. Fifteen patients had de novo AML, six AML with myelodysplasia-related changes, two AML with prior myeloproliferative neoplasm, one therapy-related myeloid neoplasm, and one myelodysplastic syndrome with excess blasts-2. No dose-limiting toxicities occurred in dose escalation cohorts. In dose expansion, six patients received panobinostat at 60 mg and nine patients at 50 mg due to recurrent grade 1 bradycardia at the 60-mg dose. The complete response (CR)/incomplete count recovery (Cri) rate was 32%. Median overall survival was 10 months: 23 months with CR/CRi versus 7.8 months without CR/CRi (log-rank P = 0.02). Median relapse-free survival was 8.2 months. Increased histone acetylation 4 and 24 hours after panobinostat was significantly associated with CR/CRi. CONCLUSIONS: Panobinostat with "7+3" for older patients with AML was well tolerated. Panobinostat 50 mg on days 1, 3, 5, and 8 starting 2 days prior to "7+3" is recommended for future studies. Panobinostat-induced increases in histone acetylation in PBMCs predicted CR/CRi.

IL-15/IL-15Rα/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice.

Engineered autologous acute myeloid leukemia (AML) cells present multiple leukemia-associated and patient-specific antigens and as such hold promise as immunotherapeutic vaccines. However, prior vaccines have not reliably induced effective antileukemic immunity, in part because AML blasts have immune inhibitory effects and lack expression of the critical costimulatory molecule CD80. To enhance induction of leukemia-specific cytolytic activity, 32Dp210 murine AML cells were engineered to express either CD80 alone, or the immunostimulatory cytokine interleukin-15 (IL-15) with its receptor α (IL-15Rα), or heterodimeric IL-15/IL-15Rα together with CD80 and tested as irradiated cell vaccines. IL-15 is a γc-chain cytokine, with unique properties suited to stimulating antitumor immunity, including stimulation of both natural killer and CD8+ memory T cells. Coexpression of IL-15 and IL-15Rα markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15Rα/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15Rα vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL-15/IL-15Rα/CD80 vaccination stimulated unprecedented antileukemic immunity enabling 80% survival, an effect that was abrogated by anti-CD8 antibody-mediated depletion in vivo. Because, clinically, AML vaccines are administered as postremission therapy, we established a novel model in which mice with high leukemic burdens were treated with cytotoxic therapy to induce remission (<5% marrow blasts). Postremission vaccination with 32Dp210-IL-15/IL-15Rα/CD80 achieved 50% overall survival in these mice, whereas all unvaccinated mice achieving remission subsequently relapsed. These studies demonstrate that combined expression of IL-15/IL-15Rα and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity.

Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches.

Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation.

Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with "high-risk" ALL uniformly require allogeneic (allo) hematopoietic cell transplantation (HCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous (auto) hematopoietic cell transplantation for high-risk patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Philadelphia chromosome-negative (Ph-) B-ALL, and 4 (14%) had T cell ALL. With a median follow-up of 41 months (range, 3 to 217), median relapse-free survival (RFS) and overall survival for the entire cohort were 3.2 and 4.2 years, respectively; at 5 years after transplantation, 42% of patients remain alive and relapse free. Using MRD detection at a threshold of ≥ 1 × 10(-6), median RFS for patients with detectable MRD was 6.5 months and was not reached for patients without detectable disease (P = .0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1 × 10(-6) (odds ratio, 23.8; confidence interval, 1.8 to 312.9; P = .0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL.

Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis.

Much attention has been directed to the physiological effects of nitric oxide (NO)-cGMP signaling, but virtually nothing is known about its hematologic effects. We reported for the first time that cGMP signaling induces human γ-globin gene expression. Aiming at developing novel therapeutics for anemia, we examined here the hematologic effects of NO-cGMP signaling in vivo and in vitro. We treated wild-type mice with NO to activate soluble guanylate cyclase (sGC), a key enzyme of cGMP signaling. Compared to untreated mice, NO-treated mice had higher red blood cell counts and total hemoglobin but reduced leukocyte counts, demonstrating that when activated, NO-cGMP signaling exerts hematopoietic effects on multiple types of blood cells in vivo. We next generated mice which overexpressed rat sGC in erythroid and myeloid cells. The forced expression of sGCs activated cGMP signaling in both lineage cells. Compared with non-transgenic littermates, sGC mice exhibited hematologic changes similar to those of NO-treated mice. Consistently, a membrane-permeable cGMP enhanced the differentiation of hematopoietic progenitors toward erythroid-lineage cells but inhibited them toward myeloid-lineage cells by controlling multiple lineage-specific transcription factors. Human γ-globin gene expression was induced at low but appreciable levels in sGC mice carrying the human ß-globin locus. Together, these results demonstrate that NO-cGMP signaling is capable of stimulating erythropoiesis in both in vitro and vivo settings by controlling the expression of multiple lineage-specific transcription factors, suggesting that cGMP signaling upregulates erythropoiesis at the level of gene transcription. The NO-cGMP signaling axis may constitute a novel target to stimulate erythropoiesis in vivo.

Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission.

In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo.

Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications.

The combined molecular adjuvant CASAC enhances the CD8+ T cell response to a tumor-associated self-antigen in aged, immunosenescent mice.

BACKGROUND: Ineffective induction of T cell mediated immunity in older individuals remains a persistent challenge for vaccine development. Thus, there is a need for more efficient and sophisticated adjuvants that will complement novel vaccine strategies for the elderly. To this end, we have investigated a previously optimized, combined molecular adjuvant, CASAC (Combined Adjuvant for Synergistic Activation of Cellular immunity), incorporating two complementary Toll-like receptor agonists, CpG and polyI:C, a class-II epitope, and interferon (IFN)-γ in aged mice. FINDINGS: In aged mice with typical features of immunosenescence, antigen specific CD8+ T cell responses were stimulated after serial vaccinations with CASAC or Complete/Incomplete Freund's Adjuvant (CFA/IFA) and a class I epitope, deriving either from ovalbumin (SIINFEKL, SIL) or the melanoma-associated self-antigen, tyrosinase-related protein-2 (SVYDFFVWL, SVL). Pentamer analysis revealed that aged, CASAC/SIL-vaccinated animals had substantially higher frequencies of H-2K(b)/SIL-specific CD8+ T cells compared to the CFA/IFA-vaccinated groups. Similarly, higher frequencies of H-2K(b)/SVL-pentamer+ and IFN-γ+ CD8+ T cells were detected in the aged, CASAC + SVL-vaccinated mice than in their CFA/IFA-vaccinated counterparts. In both antigen settings, CASAC promoted significantly better functional CD8+ T cell activity. CONCLUSION: These studies demonstrate that functional CD8+ T cells, specific for both foreign and tumour-associated self-antigens, can be effectively induced in aged immunosenescent mice using the novel multi-factorial adjuvant CASAC.

Myelodysplastic syndromes, version 2.2015.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.

A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia.

BACKGROUND: Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML. PATIENTS AND METHODS: In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) µmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion. RESULTS: Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P = .08). CONCLUSION: Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 µmol/min.

Changes in pyruvate metabolism detected by magnetic resonance imaging are linked to DNA damage and serve as a sensor of temozolomide response in glioblastoma cells.

Recent findings show that exposure to temozolomide (TMZ), a DNA-damaging drug used to treat glioblastoma (GBM), can suppress the conversion of pyruvate to lactate. To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic GBM cell populations differing only in expression of the DNA repair protein methyltransferase (MGMT), a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo. Hyperpolarized [1-((13))C]-pyruvate-based MRI was used to monitor temporal effects on pyruvate metabolism in parallel with DNA-damage responses and tumor cell growth. TMZ exposure decreased conversion of pyruvate to lactate only in MGMT-deficient cells. This effect coincided temporally with TMZ-induced increases in levels of the DNA-damage response protein pChk1. Changes in pyruvate to lactate conversion triggered by TMZ preceded tumor growth suppression and were not associated with changes in levels of NADH or lactate dehydrogenase activity in tumors. Instead, they were associated with a TMZ-induced decrease in the expression and activity of pyruvate kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism. PKM2 silencing decreased PK activity, intracellular lactate levels, and conversion of pyruvate to lactate in the same manner as TMZ, and Chk1 silencing blocked the TMZ-induced decrease in PKM2 expression. Overall, our findings showed how TMZ-induced DNA damage is linked through PKM2 to changes in pyruvate metabolism, and how these changes can be exploited by MRI methods as an early sensor of TMZ therapeutic response.

Hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of adverse events and overall survival in older allogeneic transplant recipients.

OBJECTIVES: Our goal was to evaluate the ability of the hematopoietic cell transplantation comorbidity index (HCT-CI) to predict outcomes after allogeneic stem cell transplant (SCT) within the context of an older patient population, where multiple comorbidities are common. MATERIALS AND METHODS: We performed a retrospective cohort study of SCT patients ≥50years of age at our institution, identifying 59 patients with complete HCT-CI data collected prospectively. RESULTS: HCT-CI category distribution in our sample was disproportionate, with almost half of patients having scores ≥3. High HCT-CI score (≥3 vs <3) was associated with significantly inferior OS (median OS not reached for HCT-CI <3 vs 14months for HCT-CI ≥3; hazard ratio (HR) 2.2, p=0.02). HCT-CI score was a better predictor of OS than age, performance status or conditioning intensity. When adjusted for disease relapse risk, HCT-CI score conferred a worse prognosis in the low risk group (HR 1.43, p=0.03) but not in the intermediate/high risk group (HR 1.08, p=0.65). NRM was low in the total sample (6% at one year) and was not associated with HCT-CI score. Grade 3-4 non-hematologic adverse events within the first 100days after SCT were significantly more common in the higher HCT-CI groups (p=0.02). CONCLUSIONS: In our older patient cohort with a high incidence of multiple comorbidities, HCT-CI score ≥3 was significantly associated with OS, particularly in the subset of patients with a low disease relapse risk.

Myelodysplastic syndromes: clinical practice guidelines in oncology.

The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.

Early Chk1 phosphorylation is driven by temozolomide-induced, DNA double strand break- and mismatch repair-independent DNA damage.

Temozolomide (TMZ) is a DNA methylating agent used to treat brain cancer. TMZ-induced O6-methylguanine adducts, in the absence of repair by O6-methylguanine DNA methyltransferase (MGMT), mispair during DNA replication and trigger cycles of futile mismatch repair (MMR). Futile MMR in turn leads to the formation of DNA single and double strand breaks, Chk1 and Chk2 phosphorylation/activation, cell cycle arrest, and ultimately cell death. Although both pChk1 and pChk2 are considered to be biomarkers of TMZ-induced DNA damage, cell-cycle arrest, and TMZ induced cytotoxicity, we found that levels of pChk1 (ser345), its downstream target pCdc25C (ser216), and the activity of its upstream activator ATR, were elevated within 3 hours of TMZ exposure, long before the onset of TMZ-induced DNA double strand breaks, Chk2 phosphorylation/activation, and cell cycle arrest. Furthermore, TMZ-induced early phosphorylation of Chk1 was noted in glioma cells regardless of whether they were MGMT-proficient or MGMT-deficient, and regardless of their MMR status. Early Chk1 phosphorylation was not associated with TMZ-induced reactive oxygen species, but was temporally associated with TMZ-induced alkalai-labile DNA damage produced by the non-O6-methylguanine DNA adducts and which, like Chk1 phosphorylation, was transient in MGMT-proficient cells but persistent in MGMT-deficient cells. These results re-define the TMZ-induced DNA damage response, and show that Chk1 phosphorylation is driven by TMZ-induced mismatch repair-independent DNA damage independently of DNA double strand breaks, Chk2 activation, and cell cycle arrest, and as such is a suboptimal biomarker of TMZ-induced drug action.