SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study.

BACKGROUND: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy. METHODS: We conducted a multicenter prospective observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to five time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T cell receptors (TCRs), in a subgroup. RESULTS: We enrolled 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), and chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Anti-S IgG ≥2,500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T cell recipients, respectively. SARS-CoV-2-specific T cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy immunity. CONCLUSIONS: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation three to four months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T cell therapy.

SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study (BMT CTN 2101).

Background: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood. Objective: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy. Design: Multicenter prospective observational study. Setting: 34 centers in the United States. Participants: 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), or chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients enrolled between April 2021 and June 2022. Interventions: SARS-CoV-2 vaccination as part of routine care. Measurements: We obtained blood prior to and after vaccinations at up to five time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T cell receptors (TCRs), in a subgroup. Results: Anti-S IgG and neutralizing antibody responses increased with vaccination in HCT recipients irrespective of vaccine initiation timing but were unchanged in CAR-T cell recipients initiating vaccines within 4 months. Anti-S IgG ≥2,500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T cell recipients, respectively. SARS-CoV-2-specific T cell responses were attained in 57%, 83%, and 58%, respectively. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy anti-S IgG levels. Limitations: The majority of participants were adults and received mRNA vaccines. Conclusions: These data support starting mRNA SARS-CoV-2 vaccination three to four months after allogeneic HCT, autologous HCT, and CAR-T cell therapy. Funding: National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.

Cultural and linguistic adaptation of a telephone-based cognitive-behavioral therapy (CBT) intervention to treat depression and anxiety in Hispanic cancer survivors.

PURPOSE/OBJECTIVES: The purpose of this study was to transcreate a manualized cognitive-behavioral therapy (CBT) intervention to address depression and anxiety among Hispanic cancer survivors. DESIGN/RESEARCH APPROACH: Stakeholders reviewed the CBT workbook for language, content, and cultural relevance. We designed semi-structured interview guides to elicit intervention feedback. SAMPLE/PARTICIPANTS: Stakeholder participants were Hispanic cancer survivors (n = 4), bilingual mental health providers (n = 2), and oncology professionals (n = 4). METHODS: Transcreation was conducted by initial translation of the workbook followed by incorporation of stakeholder feedback. A bilingual (Spanish and English) interviewer conducted stakeholder interviews. The study team discussed themes/suggestions before refining the workbook. FINDINGS: Stakeholders reported enthusiasm for the intervention. We gathered significant feedback regarding wording, images, and resources for the workbook. CONCLUSION: Development of culturally appropriate mental health resources for Hispanic cancer survivors is critical. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS OR POLICY: By broadening research on psychosocial care to the Hispanic population, we increase the reach of evidence-based psychological care. Future research should fully evaluate the adapted CBT intervention among Hispanic survivors.

The Transplantation Ecosystem: A New Concept to Improve Access and Outcomes for Older Allogeneic Hematopoietic Cell Transplantation Patients.

Allogeneic hematopoietic cell transplantation (HCT) is increasingly offered to older adults with hematologic malignancies, even though nonrelapse mortality remains a major concern in older patients owing to more comorbidities and greater frailty compared with their younger counterparts. The importance of patient fitness, a well-matched donor, and disease control to the success of allogeneic HCT have been well documented; however, these factors fail to account for the impact of the complex transplantation ecosystem (TE) that older adult HCT candidates must navigate. We propose a definition of the TE modeled after the social determinants of health. Furthermore, we outline a research agenda aimed at increasing understanding of the roles of individual social determinants of transplantation health in the larger ecosystem and how they may benefit or harm older adult HCT candidates. Herein we define the TE and its individual tenets, the social determinants of transplantation health. We review the available literature while incorporating the expertise of the membership of the American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Group for Aging. The membership of the ASTCT Special Interest Group for Aging identify knowledge gaps and strategies to address them for each of the described social determinants of transplantation health. The ecosystem is an essential but underappreciated pillar for transplant access and success. We put forth this novel research agenda seeking to gain a better understanding of the complexity of HCT in older adults and develop strategies to improve access to HCT, survival, and quality of life.

Real-world outcomes of adult patients with acute lymphoblastic leukemia treated with a modified CALGB 10102 regimen.

Acute lymphoblastic leukemia (ALL) is an aggressive bone marrow cancer with disparate outcomes. Data on patient outcomes in real world settings outside of clinical trials is limited. The current study reports on outcomes for 137 ALL patients who received an adult induction and consolidation regimen derived from the CALGB 10102 trial modified without alemtuzumab. Of the 137 patients, 32 were < 40 years old, 52 were between 40 and 59, and 53 were ≥ 60 years old. Overall, 109 (79.6%) patients achieved a complete remission (< 40: 96.1%, 40-59: 86.5%, and 62.3% ≥ 60 (p = 0.0002)). Progression free survival for the entire cohort was 13.5 months and by age was 19.8 months for less than 40, 23.4 months for 40 to 59 and 6.7 months for ≥ 60; p = 0.0002. Median survival was 22.1 months for the entire cohort (32.9 months for ages < 40, 26.6 months ages 40-59, 7.8 months ≥ 60, p < 0.001).

Financial burden for caregivers of adolescents and young adults with cancer.

OBJECTIVE: Adolescent and young adult (AYA) cancer survivors are vulnerable to cancer-related financial burden, which is likely shared by their caregivers. This study aims to enhance an existing conceptual model of financial burden by conducting concept elicitation interviews with caregivers to generate knowledge that can be translated to inform instrumental and psychosocial support in cancer care. METHODS: Qualitative concept elicitation interviews were conducted with 24 caregivers of AYA cancer survivors (caregivers of adolescents, n = 12; caregivers of emerging adults, n = 12) recruited from four sites. Constant comparative methods were used to identify themes, and results were interpreted and organized into domains of the conceptual model. We also explored COVID-19 related financial impacts among a subset (n = 12) of caregivers. RESULTS: Seven themes emerged, which varied by age group and strengthened the conceptualization of the model. Themes centered on: (1) direct and indirect costs of cancer; (2) impact of socioeconomic status on financial burden; (3) caregiver desire to shield AYAs from distress due to financial burden; (4) strategies to manage cancer-related costs; (5) worries about AYAs' financial future; (6) seeking and receiving financial support; and (7) navigating the healthcare system. Findings also revealed that COVID-19 exacerbates financial burden for some caregivers. CONCLUSIONS: Building upon our prior work, we have adapted the conceptual model of financial burden to reflect perspectives of AYAs, oncology providers, and now, caregivers. An important next step is to develop a reliable and valid self-report measure of financial burden among caregivers of AYA cancer survivors.

Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia.

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.

Stakeholder-informed conceptual framework for financial burden among adolescents and young adults with cancer.

BACKGROUND: Cancer and its treatments can result in substantial financial burden that may be especially distressing for adolescents and young adults (AYAs) since they are at a developmental stage focused on completing one's education and establishing independence. The purpose of this study was to develop a conceptual model of financial burden among AYA cancer patients to inform development of a financial burden measure. METHODS: In-depth concept elicitation interviews were conducted with a purposive-selected stakeholder sample (36 AYAs and 36 AYA oncology health care providers). The constant comparative method was used to identify themes that illustrate AYAs' experience of financial burden by stakeholder groups. RESULTS: Eleven financial burden themes emerged: (1) impact of socioeconomic status and age; (2) significant cancer costs; (3) indirect cost "ripple effects"; (4) limited awareness of costs (adolescents); (5) emotional impact; (6) feeling overwhelmed navigating the health care system; (7) treatment decision modifications; (8) reducing spending; (9) coping strategies; (10) financial support; and (11) long-lasting impact. The conceptual model highlights the importance of material, psychosocial, and behavioral domains of financial burden with an emphasis on phase along the cancer continuum and developmental stage in the experience of financial burden for AYAs. CONCLUSIONS: Issues presented in the voice of AYA patients and providers highlight the profound impact of financial burden in this survivor group. The next step in this work will be to develop and test a patient-reported measure of financial burden among AYA cancer survivors.

CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies.

PURPOSE OF REVIEW: Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods for prevention and management of CMV infection are urgently needed. We aim to review the new developments in diagnostics, prevention, and management strategies of CMV infection in Allo-HSCT recipients. RECENT FINDINGS: The approval of the novel anti-CMV drug letermovir in 2017 has led to an increase in the use of antiviral prophylaxis as a preferred approach for prevention in many centers. Real-world studies have shown efficacy similar to the clinical trial. CMV-specific T cell-mediated immunity assays identify patients with immune reconstitution and predict disease progression. Phase 2 trials of maribavir have shown its efficacy as preemptive therapy and treatment of resistant and refractory CMV infections. Adoptive T cell therapy is an emerging option for treatment of refractory and resistant CMV. Of the different CMV vaccine trials, PepVax has shown promising results in a phase 1 trial. SUMMARY: CMV cell-mediated immunity assays have potential to be used as an adjunctive test to develop individualized management plan by identifying the patients who develop immune reconstitution; however, further prospective interventional studies are needed. Maribavir and adoptive T cell therapy are promising new therapies for treatment of CMV infections. CMV vaccine trials for prevention are also under way.

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.

Breaking the Age Barrier: Physicians' Perceptions of Candidacy for Allogeneic Hematopoietic Cell Transplantation in Older Adults.

Despite continuing increases in the use of allogeneic hematopoietic cell transplantation (alloHCT) in older adults, no standardized geriatric assessment (GA) has been established to risk stratify for transplantation-related morbidity. We conducted a survey of transplant physicians to determine perceptions of the impact of older age (≥60 years) on alloHCT candidacy, and utilization of tools to gauge candidacy. This 23-item online cross-sectional survey was distributed to HCT physicians caring for adults in the United States between May and July 2019. Of the 770 invited HCT physicians, 175 (22.7%) completed the survey. The majority of respondents were age 41 to 60 years and male and practiced in a higher-volume teaching hospital. When considering regimen intensity, 29 physicians (17%) stated they would consider a myeloablative regimen for patients age ≥70 years, and 141 (82%) would consider reduced-intensity/nonmyeloablative conditioning for patients age ≥70 years. Almost all (90%) endorsed the need for a specialized assessment of pre-HCT vulnerabilities to guide candidacy decisions for older adults. Most physicians reported that their centers rarely (33%) or never (46%) use a dedicated geriatrician/geriatric-oncologist to assess alloHCT candidates age ≥60 years. Common barriers to performing a GA included uncertainty about which tools to use, lack of knowledge and training, and lack of appropriate clinical support staff. Many alloHCT physicians will consider alloHCT in patients up to age 75 years and not uncommonly in patients older than that. However, the application of tools and domains to assess candidacy in older adults varies widely. Incorporation of a standardized pretransplantation health assessment tool for risk stratification is a significant unmet need.

Systematic review of financial burden assessment in cancer: Evaluation of measures and utility among adolescents and young adults and caregivers.

The cost of cancer care is rising and represents a stressor that has significant and lasting effects on quality of life for many patients and caregivers. Adolescents and young adults (AYAs) with cancer are particularly vulnerable. Financial burden measures exist but have varying evidence for their validity and reliability. The goal of this systematic review is to summarize and evaluate measures of financial burden in cancer and describe their potential utility among AYAs and their caregivers. To this end, the authors searched PubMed, Embase, the Cochrane Library, CINAHL, and PsycINFO for concepts involving financial burden, cancer, and self-reported questionnaires and limited the results to the English language. They discarded meeting abstracts, editorials, letters, and case reports. The authors used standard screening and evaluation procedures for selecting and coding studies, including consensus-based standards for documenting measurement properties and study quality. In all, they screened 7250 abstracts and 720 full-text articles to identify relevant articles on financial burden. Eighty-six articles met the inclusion criteria. Data extraction revealed 64 unique measures for assessing financial burden across material, psychosocial, or behavioral domains. One measure was developed specifically for AYAs, and none were developed for their caregivers. The psychometric evidence and study qualities revealed mixed evidence of methodological rigor. In conclusion, several measures assess the financial burden of cancer. Measures were primarily designed and evaluated in adult patient populations with little focus on AYAs or caregivers despite their increased risk of financial burden. These findings highlight opportunities to adapt and test existing measures of financial burden for AYAs and their caregivers.

A Pilot Phase II Study of the Feasibility and Efficacy of Vincristine Sulfate Liposome Injection in Patients With Relapsed or Refractory Acute Myeloid Leukemia.

BACKGROUND: Resistance to therapy and a poor outcome characterize relapsed or refractory acute myeloid leukemia (AML). There is a clear need for additional palliative approaches with acceptable toxicities. Vincristine sulfate liposome injection (VSLI) confers enhanced pharmacokinetics and activity when compared to the parent compound. It is effective and well tolerated in heavily pretreated acute lymphoblastic leukemia (ALL) patients. Preclinically VSLI has activity in vincristine-resistant cancers. As relapsed or refractory AML patients would have minimal exposure to vincristine it was hypothesized that VSLI would be well tolerated and may have activity. METHODS: A pilot phase II clinical trial was conducted. Five patients with relapsed or refractory disease were treated using the Food and Drug Administration (FDA)-approved dose and schedule. RESULTS: Of the five patients treated none completed more than one cycle; there were no responses and two patients did not complete one cycle of therapy. Surprisingly, three of the five patients had treatment-related constipation, and two had neuropathy consistent with the known toxicities of VSLI. Given the toxicity and lack of response, the trial was terminated early. CONCLUSIONS: VSLI had no activity against relapsed or refractory AML in this limited, single institution dataset.

Efficacy of 10-day decitabine in acute myeloid leukemia.

The azanucleotide decitabine is used in the treatment of acute myeloid leukemia (AML). Studies have shown conflicting results with 10-day regimens used in previously untreated AML patients. Additionally, there is little data on 10-day decitabine regimens in the relapsed setting. This study investigated outcomes of 108 adult patients with AML in the upfront and relapsed setting treated with a 10-day decitabine regimen. In the upfront group, the overall response rate (ORR, CR + CRi) was 36.1% and the median overall survival (OS) was 6.6 months, while the relapsed/refractory group had an ORR of 25% with an OS of 4.8 months. When analyzed with respect to cytogenetics, the upfront group featured an ORR of 28.1% with an OS of 9.4 months in the intermediate cytogenetic cohort compared to a 40.5% ORR and an OS of 5.4 months in the unfavorable cytogenetic cohort. An analysis of the relapsed/refractory group demonstrated an ORR of 26.3% with an OS of 7.9 months for intermediate cytogenetics versus 25.0% with an OS of 1.8 months in the unfavorable cohort. While these response rates are similar to previously published data, the median OS appears shorter.

Final outcomes of escalated melphalan 280 mg/m2 with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival.

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220-260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose-response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.

A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia.

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060-73. ©2018 AACR.

Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort.

OBJECTIVES: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. METHODS: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier's curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. RESULTS: Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0-4) and higher (5-7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (≥24) groups (p = 0.19 for both). CONCLUSIONS: Despite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT.

Outcomes and changes in code status of patients with acute myeloid leukemia undergoing induction chemotherapy who were transferred to the intensive care unit.

Patients with Acute Myeloid Leukemia (AML) have compromised marrow function and chemotherapy causes further suppression. As a result complications are frequent, and patients may require admission to the intensive care unit (ICU). How codes status changes when these events occur and how those changes influence outcome are largely unknown. Outcomes for adult patients with AML, undergoing induction chemotherapy, and transferred to the ICU between January 2000 and December 2013 were analyzed. 94 patients were included. Median survival was 1.3 months. At 3 and 6 months overall survival (OS) was 27% and 18% respectively. Respiratory failure was the most common reason for transfer to ICU (88%), with 63% requiring mechanical ventilation at transfer. Other reasons included: cardiac arrest (18%), septic shock (17%), hypotension (9%), and acute renal failure (9%). The most frequent interventions were mechanical ventilation in 85%, vasopressors in 62%, and hemodialysis in 30%. Following transfer 55 patients (58%) had a change in code status. Overall, 46 patients (49%) changed from Full Code (FC) to Comfort Care (CC), 7 (7%) from FC to Do Not Resuscitate (DNR), and 2 (2%) from DNR to CC. For the entire cohort, ICU mortality (IM) was 61% and hospital mortality (HM) was 71%. For FC or DNR patients, IM was 30% and HM was 41%. For CC patients, IM was 90% and HM was 100%. Overall, 27 patients (29%) survived to discharge. Of those discharged, 22 (81%) were alive at 3 months and 17 (63%) were alive at 6 months. In conclusion, patients that required ICU admission during induction chemotherapy have a poor prognosis. Code status changed during the ICU stay for the majority of patients and always to a less aggressive status.

Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia.

The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.