Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG).

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients' sex in analyses of AML biology and prognostication.

Outcomes After Salvage Autologous Hematopoietic Cell Transplant for Patients With Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience.

BACKGROUND: The role of salvage autologous hematopoietic cell transplantation (sAHCT2) for patients with relapsed/refractory multiple myeloma (RRMM) in the era of modern therapeutics is unclear. As prospective data is limited, we conducted a retrospective analysis to determine the outcomes of sAHCT2. PATIENTS AND METHODS: We conducted a single-institution, retrospective analysis of patients who received sAHCT2 at The Ohio State University from 2000 to 2018. Patients who received a second transplant as part of a planned tandem or autologous-allogeneic transplant were excluded. RESULTS: Fifty-seven patients were treated with sAHCT2. Patients had a median of 2 lines of therapy after AHCT1 prior to their sAHCT2; 70% had prior immunomodulatory imide drugs, 82% had prior proteasome inhibitor, and 20% had prior anti-CD38 monoclonal antibodies as part of re-induction therapy. Forty-two percent of patients attained ≥VGPR prior to sAHCT2. Seventy-four were treated with melphalan 200 mg/m2 as conditioning regimen before infusion of a median of 3.8 × 106 CD34+ cells/kg. Fifty-eight percent patients had maintenance therapy and 81% patients attained CR/VGPR as the best response after sAHCT2. The median PFS and OS after sAHCT2 were 1.6 and 3.6 years, respectively. On multivariable analysis, high-risk cytogenetics, not having attained CR/VGPR, and having more than 2 lines of therapy post-AHCT1 were associated with inferior PFS. Melphalan 140 mg/m2 compared to melphalan 200 mg/m2 and no maintenance therapy compared to maintenance therapy were not associated with inferior PFS. There was no transplant-related mortality in this patient cohort. CONCLUSIONS: For MM patients deriving durable remission after their AHCT1, sAHCT2 was safe and resulted in deep and durable remissions.

Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: a multicenter study.

We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.

The Incidence of Invasive Fungal Infections in Patients With AML Treated With a Hypomethylating Agent.

BACKGROUND: Newly diagnosed patients with acute myeloid leukemia (AML) who receive induction with a hypomethylating agent (HMA) are often neutropenic with an increased risk for invasive fungal infections (IFIs). This study analyzed the incidence and risk factors for IFIs in these patients, evaluated clinical patterns in antifungal prophylaxis, and assessed the diagnostic utility of tests in this setting. PATIENTS AND METHODS: We studied 117 newly diagnosed patients with AML treated with HMAs at our center, divided into groups based on concern for IFI (cIFI: all possible, probable, and proven IFIs) versus no concern for IFI. The Fisher exact test compared patients with cIFI versus without, and a multivariable logistic regression model estimated odds for cIFI. RESULTS: Sixty-seven (57%) patients had cIFI, with 48 possible IFIs, 17 probable, and 2 proven cases. There was no difference in incidence based on home zip code, but the presence of chronic obstructive pulmonary disease was highly associated with cIFI (P = .001), as was male gender (P = .01). Neutropenia at treatment initiation was borderline in significance (P = .08). In diagnostics, 9% of patients had positive serum fungal markers, and 30 patients underwent bronchoscopy, with only 27% of cases yielding positive results. There was a difference in treatment regimens between patients receiving antifungal prophylaxis with mold coverage versus without mold coverage with respect to cIFI (P = .04). CONCLUSIONS: cIFI in patients with AML treated with HMAs remains significant, especially in males and those with chronic obstructive pulmonary disease, who were found to be at higher risk. This may prompt clinicians to consider anti-mold prophylaxis in this setting.

AL amyloidosis: The effect of fluorescent in situ hybridization abnormalities on organ involvement and survival.

BACKGROUND: Systemic light chain (AL) amyloidosis is a clonal plasma-cell neoplasm that carries a poor prognosis. Although AL amyloidosis and Multiple Myeloma (MM) can co-exist and share various cytogenetic chromosomal abnormalities, little is known about Fluorescent in situ hybridization (FISH) and its prognostic relevance in AL amyloidosis. AIM: The study aims to evaluate the most prevalent FISH cytogenetic abnormalities in AL patients as independent prognostic factors, and assess the impact of cytogenetics on the survival of high-risk cardiac AL patients. MATERIALS & METHODS: This retrospective study reviewed 113 consecutive AL patients treated at The Ohio State University (OSU). Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS). Kaplan Meier curves were used to calculate PFS and OS. The log-rank test and Cox proportional hazard models were used to test the equality of survival functions and further evaluate the differences between groups. RESULTS: FISH abnormalities were detected in 76% of patients. Patients with abnormal FISH trended toward lower overall survival (OS) (p=0.06) and progression free survival (PFS) (p=0.06). The two most prevalent aberrations were translocation t(11;14) (39%) and hyperdiploidy-overall (38%). Hyperdiploidy-overall was associated with worsening PFS (p=0.018) and OS (p=0.03), confirmed in multivariable analysis. Patients with del 13q most frequently had cardiac involvement (p=0.006) and was associated with increased bone marrow plasmacytosis (p=0.02). Cardiac AL patients with no FISH abnormalities had much improved OS (p=0.012) and PFS (p=0.018) CONCLUSIONS: Our findings ultimately reveal the association of hyperdiploidy on survival in AL amyloidosis patients, including the high-risk cardiac AL population.

AL Amyloidosis: The Effect of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes.

BACKGROUND: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic light chain (AL) amyloidosis. While maintenance post ASCT in multiple myeloma is now standard, the decision to utilize maintenance in AL amyloidosis remains largely unexplored. The present study aims to determine the prognostic significance of utilizing maintenance therapy following ASCT and assess the impact of fluorescent in situ hybridization (FISH) abnormalities, bone marrow plasma cell burden (BMPC), and degree of organ involvement on this decision. METHODS AND RESULTS: This is a retrospective analysis of fifty AL amyloidosis patients who underwent ASCT at The Ohio State University. Twenty-eight patients received maintenance and twenty-two did not. Kaplan-Meier survival analysis was used to compare the effect of maintenance therapy with no significant difference in PFS (p = 0.66) and OS (p = 0.32) between the two groups. There was no difference in survival based on maintenance when further categorized by FISH, PFS (p = 0.15), and OS (p = 0.65); BMPC ≥ 10%, PFS (p = 0.49), and OS (p = 0.32); or with 2 or more organs involved, PFS (p = 0.34) and OS (p = 0.80). CONCLUSION: Maintenance therapy post ASCT did not impact PFS or OS when categorized by FISH abnormalities, increasing BMPC, or ≥2 organs involved in AL amyloidosis patients.

Hybrid uranyl-carboxyphosphonate cage clusters.

Two new hybrid uranyl-carboxyphosphonate cage clusters built from uranyl peroxide units were crystallized from aqueous solution under ambient conditions in approximately two months. The clusters are built from uranyl hexagonal bipyramids and are connected by employing a secondary metal linker, the 2-carboxyphenylphosphonate ligand. The structure of cluster A is composed of a ten-membered uranyl polyhedral belt that is capped on either end of an elongated cage by five-membered rings of uranyl polyhedra. The structure of cluster B consists of 24 uranyl cations that are arranged into 6 four-membered rings of uranyl polyhedra. Four of the corresponding topological squares are fused together to form a sixteen-membered double uranyl pseudobelt that is capped on either end by 2 topological squares. Cluster A crystallizes over a wide pH range of 4.6-6.8, while cluster B was isolated under narrower pH range of 6.9-7.8. Studies of their fate in aqueous solution upon dissolution of crystals by electrospray ionization mass spectrometry (ESI-MS) and small-angle X-ray scattering (SAXS) provide evidence for their persistence in solution. The well-established characteristic fingerprint from the absorption spectra of the uranium(VI) cations disappears and becomes a nearly featureless peak; nonetheless, the two compounds fluoresce at room temperature.

Uranyl peroxide pyrophosphate cage clusters with oxalate and nitrate bridges.

Two complex cage clusters built from uranyl hexagonal bipyramids and multiple types of bridges between uranyl ions, U(30)Py(10)Ox(5) and U(38)Py(10)Nt(4), were crystallized from aqueous solution under ambient conditions. These are built from 30 uranyl hexagonal bipyramids, 10 pyrophosphate groups, and five oxalate bridges in one case, and 38 uranyl hexagonal bipyramids, 10 pyrophosphate groups, and four nitrate groups in the other. The crystal compositions are (H(3)O)(10)Li(18)K(22)[(UO(2))(30)(O(2))(30)(P(2)O(7))(10)(C(2)O(4))(5)](H(2)O)(22) and Li(24)K(36)[(UO(2))(38)(O(2))(40)(OH)(8)(P(2)O(7))(10)(NO(3))(4)](NO(3))(4)(H(2)O)(n) for U(30)Py(10)Ox(5) and U(38)Py(10)Nt(4), respectively. Cluster U(30)Py(10)Ox(5) crystallizes over a narrow range of solution pH that encourages incorporation of both oxalate and pyrophosphate, with incorporation of oxalate only being favored under more acidic conditions, and pyrophosphate only under more alkaline conditions. Cluster U(38)Py(10)Nt(4) contains two identical lobes consisting of uranyl polyhedra and pyrophosphate groups, with these lobes linked into the larger cluster through four nitrate groups. The synthesis conditions appear to have prevented closure of these lobes, and a relatively high nitrate concentration in solution favored formation of the larger cluster.