Citations

SummaryReduced‐intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo‐HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)‐matched sibling or unrelated donor allo‐HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0·01. There were no significant differences between regimens in risk for non‐relapse mortality (NRM) (P = 0·54), relapse/progression (P = 0·02) or progression‐free survival (PFS) (P = 0·14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo‐HCT (HR = 0·28; 95% CI = 0·10–0·73; P = 0·009), but beyond 11 months post allo‐HCT it was associated with a significantly higher risk of mortality, (HR = 2·46; 95% CI = 0·1.32–4·61; P = 0·005). Four‐year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0·64), respectively. These data confirm the choice of RIC for allo‐HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo‐HCT (possibly due to late NRM events).

Abstract Background: We recently reported on MPLW515L/K mutations in 1182 patients with myeloid disorders (Blood, First Edition July 25, 2006) and found low frequency occurrence in in agnogenic myeloid metaplasia (AMM) (~5%) and essential thrombocythemia (ET) (~1%), but not polycythemia vera (PV). Of the 20 MPLW515L/K-positive patients in that series, 6 (30%) also carried a low burden of the JAK2V617F mutation. Studies of mutation prevalence in individuals with clonal granulopoiesis as well as familial myeloproliferative disorders (MPD) studies suggest that these mutations (JAK2V617F) may be acquired as secondary genetic events. Aim: to gain additional insight regarding the aforementioned two mutations and MPD pathogenesis by determining (i) concordance between mutation expression and clonal hematopoiesis, (ii) the instructive role of each mutation in determining lineage fate, iii) differences in pattern and lineage restriction of these mutations between various MPD, and (iv) chronology of clonal emergence and clonal dominance for the 2 mutations. Methods: Sixteen MPD patients were studied (13 JAK2V617F+ and 3 MPLW515L/K+); 9 had PV (all JAK2V617F+), 2 ET (both JAK2V617F+), 1 CMML (JAK2V617F+), and 4 AMM (2 MPLW515K+, and one each with MPLW515L and JAK2V617F). CD34+ progenitor cells were plated in methylcellulose and resulting hematopoietic colonies were scored on day 10–12. Colonies were obtained with (all patients) and without (10 patients; 5 with PV, 1 ET, and 4 AMM) cytokine support. Individual colonies were screened for presence of either mutation by DNA sequencing. In addition, MPLW515L/K analysis was performed in T and B lymphocytes in 3 informative cases. Finally, serially stored bone marrow was examined in 3 patients with co-expression of MPL515 and JAK2V617F mutations. Results: A total of 552 hematopoietic colonies from 16 MPD patients were genotyped. We found cohabitation of both mutation-positive and mutation-negative endogenous colonies in PV as well as other MPD. For JAK2V617F+ patients, the majority (75–100%) of erythropoietin-independent erythroid colonies (EEC) but not endogenous granulocyte colonies (20–70%) were mutation-positive. In contrast, no EEC were obtained from progenitors from the 3 MPLW515L/K+ patients. For 2 of the 3 patients, the endogenous myeloid colonies were predominantly mutation-positive (~90%). A mixed allele pattern (homozygous and/or heterozygous) was seen with both mutations regardless of MPD phenotype, but the overall mutant colony burden was higher with MPLW515L/K mutations relative to JAK2V617F. When such testing was possible, MPL515 mutations were detected in T-lymphocytes (2 of 3 patients) as well as B-lymphocytes (2 of 2 patients). Finally, among 3 patients carrying both mutations, serial marrow studies (25 time points over 4–8 years) revealed the occurrence of both mutations at diagnosis and persistent dominance of MPLW515L/K over JAK2V617F over time. Conclusions: Our observations provide direct evidence for clonal hematopoiesis that antedates acquisition of either MPLW515L/K or JAK2V617F that bias towards myeloid and erythroid fates, respectively. Furthermore, both mutations appear to occur early in the disease course and lineage studies suggest a hierarchically earlier stem cell origin for MPLW515L/K as compared to JAK2V617F.

Abstract Purpose: Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits. Patients and Methods: We report the Southwest Oncology Group randomized phase II trial (S1304) comparing twice weekly low-dose (27 mg/m2; arm 1) to high-dose carfilzomib (56 mg/m2; arm 2), both with dexamethasone, administered for 12 cycles (11 months) for relapsed and/or refractory multiple myeloma with up to six prior lines of therapy (NCT01903811). The primary endpoint was progression-free survival (PFS), and patients on arm 1 could cross-over to arm 2 after progression on treatment. Results: Among 143 enrolled patients, of whom 121 were eligible and analyzable, the overall response rate was 42.8%, with no significant difference between the arms (P = 0.113). Also, neither the median PFS [5 months and 8 months, respectively; HR, 1.061; 80% Wald confidence interval (CI), 0.821–1.370; P = 0.384] nor the median overall survival were significantly different (26 and 22 months, respectively; HR, 1.149, 80% Wald CI, 0.841–.571; P = 0.284). Sixteen patients crossed over to arm 2 with a median PFS benefit of 3 months. Certain adverse events (AE) were more frequent in arm 2, including fatigue, thrombocytopenia, and peripheral neuropathy, but there was no significant difference in cardiopulmonary AEs. Conclusions: This randomized trial did not support a benefit of fixed duration, twice weekly 56 mg/m2 dosing of carfilzomib over the 27 mg/m2 dose for the treatment of relapsed and/or refractory multiple myeloma. However, treatment to progression in earlier patient populations with high-dose carfilzomib using different schedules should still be considered as part of the standard of care.

Importance Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain. Objective To determine whether cumulative BP levels explain racial differences in cognitive decline. Design, Setting, and Participants Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018. Main Outcomes and Measures The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function. Exposures Race (black vs white). Results Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (−0.03 points per year faster [95% CI, −0.05 to −0.01]; P = .004) and memory (−0.08 points per year faster [95% CI, −0.11 to −0.06]; P &amp;lt; .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P &amp;lt; .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (−0.018 points per year faster per each 10–mm Hg increase [95% CI, −0.023 to −0.014]; P &amp;lt; .001), memory (−0.028 points per year faster per each 10–mm Hg increase [95% CI, −0.035 to −0.021]; P &amp;lt; .001), and executive function (−0.01 points per year faster per each 10–mm Hg increase [95% CI, −0.014 to −0.007]; P &amp;lt; .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (−0.01 points per year [95% CI, −0.03 to 0.01]; P = .56) and memory (−0.06 points per year [95% CI, −0.08 to −0.03]; P &amp;lt; .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P &amp;lt; .001). Conclusions and Relevance These results suggest that black individuals’ higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

The medial sural artery perforator (MSAP) flap is a versatile fasciocutaneous flap that has been used successfully in the reconstruction of defects across the body. In specific cases, it may prove superior to more commonly used options (e.g., anterolateral thigh flap and radial forearm free flap). Historically, a disadvantage of the MSAP flap is the relatively small surface area it provides for reconstruction. We recently encountered a patient with extensive pelvic injuries from prior trauma resulting in significant scarring and contracture of the groin, tethering of the penis, and loss of the scrotum and one testicle. The patient was unable to achieve erection from tethering and his remaining testicle had been buried in the thigh. In considering the reconstructive options, he was not a suitable candidate for a thigh-based or forearmbased flap. An extended MSAP flap measuring 25 cm×10 cm was used for resurfacing of the groin and pelvis as well as for the formation of a neoscrotum. This report is the first to document an MSAP flap utilized for simultaneous groin resurfacing and scrotoplasty. Additionally, the dimensions of this flap make it the largest recorded MSAP flap to date.

AbstractPeyronie’s disease is a common yet poorly understood condition characterized by penile pain, curvature, sexual dysfunction and psychological bother. Peyronie’s disease represents a penile wound healing disorder, and is thought to arise from exuberant scarring in response to penile trauma in genetically predisposed men. In the absence of active treatment, the majority of men experience stable or worsening symptoms, with few reporting spontaneous resolution in penile curvature or other deformity. In contrast, penile pain improves or resolves in the majority of men. Treatment options vary based on symptom severity and stability. Several oral therapies are commonly prescribed, although to date there are no strong data to support any oral agents as monotherapy for Peyronie’s disease. Other options including penile traction therapy and intralesional injections result in modest improvements for many patients, particularly when used early after symptom onset. Penile straightening through approaches, such as penile plication and plaque incision or partial excision and grafting, represent the most rapid and reliable approach to correct penile curvature once the symptoms have stabilized. Side‐effects vary based on the type of surgery carried out, and include penile shortening, sensation changes and erectile dysfunction in the minority of men. In patients with drug refractory erectile dysfunction and Peyronie’s disease, placement of a penile prosthesis will address both issues, and is associated with high levels of patient satisfaction. The current review provides a practical approach to the modern evaluation and management of patients presenting with Peyronie’s disease.

Abstract There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P &lt; .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

TPS8057 Background: Multiple myeloma (MM) is the second most prevalent blood cancer, representing approximately 1% of all cancers. Although overall survival has improved in recent years due to new approved agents, the vast majority of MM patients (pts) ultimately stop responding to treatment. Moreover, about a quarter of MM pts characterized as “high risk” experience limited benefit from existing treatments. Seminal genomic sequencing research efforts, such as the MMRF CoMMpass study, have highlighted that a large number of MM cases harbor potentially actionable oncogenic molecular alterations and published reports on small numbers of cases suggest that Precision Medicine (PM) interventions clinically targeting such actionable drivers may benefit MM pts. These results suggest that PM approaches in MM are possible and should be further studied clinically. To that end, we have launched MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual pt’s genomics. Methods: This study is a Phase I-II, multicenter master protocol in functional high risk MM patients (i.e patients having progressed from baseline treatment within 18 months without maintenance or 3 years on maintenance) with 1-3 prior lines of therapy. Patients are screened for actionable genomic alterations on the CLIA-grade MI-ONCOSEQ platform. Patients with actionable alterations are assigned to the appropriate targeted agent used in combination with a backbone regimen ixazomib, pomalidomide and dexamethasone (IPd), whereas patients without such alterations go on an immune arm (see Table). Inclusion criteria include measurable disease (as measured by M-protein and FLC) and acceptable hematologic and metabolic functions. A maximum of 12 evaluable pts will be accrued onto the phase I portion of each arm and an additional 21 evaluable phase II pts will be accrued onto each arm for a total of 27 evaluable pts at the MTD combination dose. The primary objective of the study is to evaluate ORR per IMWG consensus criteria. Secondary objectives are to assess adverse events (AEs), progression-free survival, and overall survival (OS). Experimental correlative aims include assessing molecular or clonal response, molecular and immune signatures of resistance/response, MRD. Clinical trial information: NCT03732703. [Table: see text]

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]

8016 Background: MAIA, an ongoing phase 3 trial of transplant-ineligible patients (pts) with NDMM, demonstrated significant improvement in progression-free survival with D-Rd vs Rd alone. Assessment of pt-reported outcomes alongside efficacy endpoints provides pt perspective on their quality of survival and overall value of HRQoL while on treatments (tx). Methods: The EORTC QLQ-C30 and EQ-5D-5L questionnaires were completed by pts using an electronic device at baseline and every 3 mo during tx; interim results are presented for first 12 mo. Tx effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature. Results: Compliance rates were high and comparable at baseline ( > 90%) and through month 12 ( > 80%) for both groups (D-Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D-Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D-Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: -0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D-Rd was also observed in EQ-5D-5L Visual Analog Scale (VAS) scores (LS mean change; D-Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D-Rd. Of note, meaningful differences were observed between the tx groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D-Rd (LS mean change at cycle 3; D-Rd: -17.9 [95% CI: -20.7, -15.0], Rd: -11.0 [95% CI: -14.0, -8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D-Rd. There was a decline in cognitive functioning at cycle 12 in both tx arms, with no statistically significant differences between groups. Conclusions: Faster and sustained improvement in HRQoL was observed in pts treated with D-Rd vs Rd with similar findings reflected across pain subscale. Clinical trial information: NCT02252172.