Isatuximab for the treatment of multiple myeloma.

Isatuximab is an IgG1 monoclonal antibody targeting CD38 that has received regulatory approval in combination regimens for patients with relapsed/refractory multiple myeloma. CD38 is an antigen with high surface expression on multiple myeloma cells. While daratumumab holds most of the market share for this drug class, isatuximab offers several unique aspects including a mechanism of action that may involve more direct myeloma-cell inhibition and killing and less reliance on cross-linking and immune effector cells, as well as subgroup data from pivotal trials showing notable efficacy in populations with renal impairment, high-risk cytogenetics and the elderly. While the administration of the drug remains intravenous, studies of fixed-volume infusion and rapid infusion may improve drug administration convenience. Ongoing studies are examining isatuximab in combination with other immune therapies and cellular therapies, conventional chemotherapy and across other disease entities.

Daratumumab for the treatment of multiple myeloma.

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma. Further investigations are underway to continue to expand the reach of daratumumab, including large phase III collaborative trials to assess the efficacy of daratumumab as part of post-transplant maintenance and its impact on smoldering myeloma. The recent introduction of a subcutaneous formulation of daratumumab with proven noninferiority will improve the convenience and accessibility of the drug. In this review, we examine the preclinical development of daratumumab, its pharmacology and clinical investigations that demonstrated its safety and efficacy. Furthermore, we discuss the outstanding questions related to daratumumab and ongoing clinical trials seeking to answer them.

Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy.

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.

Donor-lymphocyte infusion following haploidentical hematopoietic cell transplantation with peripheral blood stem cell grafts and PTCy.

Donor-lymphocyte infusion (DLI) for relapse following haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) has been described in recipients of bone marrow grafts, but not recipients of G-CSF mobilized peripheral blood (PB) grafts. We retrospectively identified patients who underwent DLI following PB-haploHCT with PTCy for relapse, or loss of chimerism (LOC). Twelve patients (57%) received DLI for hematologic relapse/persistent disease, seven (33%) for extramedullary relapse and two (10%) for LOC. Sixteen (76%) received chemotherapy prior to DLI, which did not correlate with response. The most common first dose was 1 × 106 CD3+ cells/kg. Two patients developed grade I aGvHD post DLI, one had grade II and two had grade III. One developed mild skin cGvHD 1361 days post DLI. Pre-DLI aGvHD predicted post-DLI aGvHD (P=0.025). Six patients achieved CR after DLI for overt relapse, one achieved full donor chimerism after LOC. Patients with LOC or EM relapse had superior relapse-free survival following DLI (P=0.029). DLI following PB-haploHCT with PTCy is a viable salvage therapy for overt relapse or LOC without a substantial increase in GvHD, and donor lymphocytes may be collected simultaneously with graft collection to facilitate availability in patients at high risk of relapse.

Angiotensin II and sympathoactivation in heart failure.

Excessive activity of the sympathetic nervous system (SNS) contributes to the development and progression of the syndrome of congestive heart failure (CHF) in patients with decreased left ventricular function. The factors underlying chronic sympathoactivation are poorly understood, particularly in stable patients. This review summarizes both clinical and experimental data regarding the effects of angiotensin II (A-II) on the activity of the SNS. The focus is on both the direct effects of A-II on the SNS and an indirect effect medicated through alteration in function of the baroreflex. Available evidence is consistent with a potentially important effect of A-II on SNS activity, perhaps most likely via the baroreflex. Important issues regarding the direct effect of A-II on regional SNS activity, and on the physiological relevance of effects seen only at high plasma concentration of A-II remain to be fully elucidated.

Regulation of regional norepinephrine spillover in heart failure: the effect of angiotensin II and beta-adrenergic agonists in the forearm circulation.

BACKGROUND: Prejunctional receptors for angiotensin II (A-II) and norepinephrine (NE) have been reported to facilitate NE release. If operative in patients with congestive heart failure (CHF), such receptors could participate in positive feedback cycles amplifying sympathoactivation. METHODS AND RESULTS: A-II and isoproterenol (ISO) would increase regional NE spillover via facilitation of presynaptic release of NE in the forearm circulation of patients with chronic stable CHF. A-II, ISO, and nitroprusside (NP) were sequentially infused into the brachial arteries of 10 patients with chronic stable CHF, which was attributed to dilated cardiomyopathy. Forearm blood flow (FBF) was measured via plethysmography and regional spillover of NE was measured by using the isotope dilution method of Esler. A-II (5 ng/min) produced a nonsignificant decline in FBF (1.87+/-0.14 to 1.46+/-0.1 mL/100 g/min, P = .07) and did not change regional NE spillover (418+/-128 to 409+/-121 ng/min). ISO increased FBF from 1.6+/-0.12 to 4.3+/-0.7 mg/100 g/min (P < .001). Regional NE spillover increased from 337+/-86 to 856+/-300 ng/min (P < .001). Venous NE and regional extraction of NE did not change. NP increased FBF from 2.0+/-0.3 to 6.3+/-1.2 mL/100 g/min (P < .001; P = NS v change with ISO) and also increased regional NE spillover (301+/-99 to 712+/-288 ng/min, P < .001; P = NS v change with ISO). As with ISO, venous NE and extraction of NE were not altered. CONCLUSIONS: Mild vasoconstrictor infusions of A-II do not increase regional NE spillover in the forearm circulation of patients with CHF. The beta-adrenergic agonist ISO does increase regional spillover, but the effect seems to be primarily related to flow rather than presynaptic stimulation of NE release. These data argue against an important positive feedback loop involving A-II and NE on sympathoactivation, at least with the dosages of the agonists studied and in the limb circulation in chronic stable CHF.

Effect of amlodipine on norepinephrine kinetics and baroreflex function in patients with congestive heart failure.

BACKGROUND: The use of calcium channel blocking drugs is controversial in heart failure, partly because of concerns about neurohormonal stimulation. Preliminary data suggest that the newer agent amlodipine may be useful in this syndrome. Suppression of sympathetic activity either directly or by sensitized baroreflex function could be contributing factors to the clinical use of this drug. OBJECTIVE: To assess the effect of short-term amlodipine therapy on baseline measures of sympathetic activity and baroreflex function in patients with chronic stable congestive heart failure (CHF). METHODS: Seven patients with chronic CHF (New York Heart Association functional class II or III, moderate to severe reduction in left ventricular systolic function) were studied. All patients underwent baroreflex testing with head-up tilt, head-down tilt, and head-down tilt with phenylephrine infusion. Heart rate, mean arterial pressure, forearm blood flow and resistance, and plasma norepinephrine (NE) kinetics were assessed at baseline and after each baroreflex perturbation on three occasions: a control test and after 10 days each of placebo and amlodipine therapy. RESULTS: Plasma NE and NE spillover did not significantly increase after amlodipine administration compared with control and placebo tests (488 +/- 119 pg/ml vs 350 +/- 85 and 325 +/- 87 pg/ml). In three subjects, plasma NE levels were essentially unchanged, whereas in four they rose markedly (289 +/- 87 pg/ml at control vs 551 +/- 158 pg/ml). There was no difference in the response of any variable during baroreflex perturbations after amlodipine administration compared with control and placebo tests. One subject who tolerated head-down tilt coupled with phenylephrine administration during the control and placebo tests became markedly short of breath during the same intervention after amlodipine administration. Plasma NE levels in this patient had risen markedly while receiving amlodipine and were not appropriately suppressed during the baroreflex loading maneuver. CONCLUSIONS: Short-term therapy with amlodipine does not suppress sympathetic activity or alter efferent responses to baroreflex perturbation in patients with stable chronic CHF. Significant increases in plasma NE and NE spillover and abnormal responses to baroreflex stimulation are possible after administration of this drug. The relevance of these findings to studies in larger number of patients requires further study.

Arginine vasopressin and baroreflex function after converting enzyme inhibition in normal humans.

Arginine vasopressin (AVP) has been shown to interact with sinoaortic and cardiac reflexes under selected experimental conditions. In humans, there is no evidence that AVP potentiates reflex function at modestly increased plasma levels, except possibly if the angiotensin-converting enzyme (ACE) is inhibited. The objective of this study was to test the hypothesis that a modest physiological increase in plasma AVP would potentiate the responses of heart rate (HR), forearm vascular resistance (FVR), plasma norepinephrine (NE), or systemic NE spillover to baroreflex unloading and loading after pretreatment with lisinopril in healthy human volunteers. Seven normal young men were studied on three occasions. Baseline HR, FVR, and steady-state NE kinetics were established, and AVP or vehicle (5% dextrose in water) was infused for 15 min double-blind on the first 2 days. Baroreflexes were then perturbed as follows: 15 min 60 degrees head-up tilt, 15 min 30 degrees head-down tilt plus 1,000 ml normal saline infusion, 15 min 30 degrees head-down tilt plus phenylephrine titrated to raise mean arterial pressure 10-15 mmHg. The study was repeated on a third day 12 h after 5 mg of lisinopril. Five additional subjects underwent similar baroreflex study on 2 days with only lisinopril and placebo. Before baroreflex deactivation and activation in the absence of lisinopril, AVP infusion had no hemodynamic or neurohormonal effects. During AVP infusion after lisinopril, HR decreased from 67 +/- 6.5 to 62 +/- 4.5 beats/min (P < 0.05). AVP had no effect on the response of any variable during baroreflex perturbation relative to vehicle, either with or without lisinopril. Lisinopril had no independent effect on these responses in the additional five subjects. At modestly increased plasma levels, AVP did not affect the responses of HR, FVR, plasma NE, or systemic NE spillover to baroreflex deactivation and activation. After lisinopril, AVP infusion produced a modest bradycardia but still had no significant positive effect on either response. These data suggest that inhibition of the angiotensin-converting enzyme may unmask mild direct or vagally mediated effects of AVP on HR but does not unmask baroreflex potentiation.

Effect of amlodipine and felodipine on sympathetic activity and baroreflex function in normal humans.

Baroreflex sensitization and direct sympatholytic effects have been suggested as contributing mechanisms to the effects of dihydropyridine calcium channel blockers in hypertension and heart failure. In this study, we tested the hypothesis that either amlodipine or felodipine would decrease norepinephrine levels and enhance cardiac, peripheral vascular, or sympathetic responses to baroreflex perturbation in healthy humans. Six healthy male volunteers aged 21 to 40 participated. Heart rate, forearm blood flow, arterial pressure, and norepinephrine kinetics were assessed in the supine position, after 15 min of 60 degrees head-up tilt, after 15 min of 30 degrees head-down tilt, and after 15 min head-down tilt with phenylephrine infused to raise mean arterial pressure 10 to 15 mm Hg. Studies were conducted double-blind on 3 different days 8 to 12 h after placebo, 5 mg amlodipine, and 10 mg felodipine. Resting heart rate, mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and norepinephrine spillover were not affected by amlodipine or felodipine. During upright tilt, head-down tilt, and phenylephrine, each variable increased and decreased as expected after placebo. There was no effect of either amlodipine or felodipine on any response to any maneuver. Baseline sympathetic activity as reflected by plasma norepinephrine and norepinephrine spillover are not altered by either amlodipine or felodipine. Neither drug acutely sensitizes baroreflex function in normal humans over the degree of perturbation produced in these protocols.

Angiotensin II inhibits the forearm vascular response to increased arterial pressure in humans.

OBJECTIVES: This study tested the hypothesis that angiotensin II may inhibit the forearm vascular resistance response to an increase in arterial pressure in normal humans. BACKGROUND: Angiotensin II inhibits baroreflex-mediated reductions in heart rate and peripheral sympathetic activity during increases in arterial pressure in experimental animals. If present in humans, such effects could contribute to the pathophysiologic role of angiotensin II in hypertension and heart failure. METHODS: Two investigations were performed. In the first, forearm vascular resistance responses were compared during equipressor infusions of angiotensin II and phenylephrine. In the second, heart rate, forearm vascular resistance and systemic venous norepinephrine spillover responses were compared during head-down tilt and head-down tilt plus phenylephrine with concomitant angiotensin II or vehicle infusions. RESULTS: In the first study, forearm vascular resistance increased from 44 +/- 12 (mean +/- SD) to 54 +/- 13 U (p < 0.05) during angiotensin II but did not change during phenylephrine infusions (39 +/- 8.5 to 40 +/- 14 U) that increased mean arterial pressure comparably (88 +/- 9.8 to 103 +/- 14 mm Hg during angiotensin II, p < 0.001; 91 +/- 7.6 to 104 +/- 9.2 mm Hg during phenylephrine, p < 0.001). In the second study, the decrease in heart rate and forearm vascular resistance during the combination of head-down tilt and phenylephrine were both attenuated during concomitant angiotensin II compared with vehicle infusions: delta HR/delta MAP = -2.2 beats/min per mm Hg during vehicle and -0.87 beats/min per mm Hg during angiotensin II (p = 0.07); delta FVR/delta MAP = -2.8 U/mm Hg during vehicle and -0.19 U/mm Hg during angiotensin II (p = 0.01), where delta HR = change in heart rate; delta MAP = change in mean arterial pressure; and delta FVR = change in forearm vascular resistance. Norepinephrine spillover declined during vehicle infusions (612 +/- 367 to 418 +/- 196 ng/min, p < 0.05) but not during angiotensin II infusions despite a greater increase in mean arterial pressure when the subpressor angiotensin II was combined with head-down tilt and phenylephrine (6.0 +/- 7.0 mm Hg during vehicle; 14 +/- 9.4 mm Hg during angiotensin II, p < 0.01). CONCLUSIONS: Both pressor and nonpressor infusions of angiotensin II immediately inhibit the forearm vascular response to mild baroreflex loading in normal humans. If present over the long term, such effects could contribute to inappropriate peripheral resistance in diseases such as hypertension and congestive heart failure.

Angiotensin II potentiates the arterial pressure response to volume loading in humans.

Angiotensin II (AII) has many potential effects on blood pressure regulation in addition to direct vasoconstriction. This study tested the hypothesis that minimally pressor infusions of AII, which themselves exert minimal effects on blood pressure, might significantly perturb the pressure response to hypertonic volume expansion in healthy humans. Accordingly, 3% saline was infused at 0.1 mL/kg/min in 13 healthy volunteers, both with and without concomitant AII infusion (2 ng/kg/min) on separate days. On a third day, AII was infused alone for 2 h in eight of these subjects. Eight subjects also were studied with 3% saline plus concomitant phenylephrine infusion as a "positive control." AII and phenylephrine exerted similar, small effects on mean arterial pressure (3.3 +/- 1.5 v 3.0 +/- 1.0 mm Hg, P = NS) before the infusion of AII. When 3% saline was infused alone, mean arterial pressure did not rise significantly. In the presence of AII, mean arterial pressure rose from 89 +/- 10 to 97 +/- 11 mm Hg (P < .01 v control; P < .05 v 3% saline alone). In the presence of phenylephrine, the mean arterial pressure did not increase during 3% saline infusion, similar to the results during 3% saline infusion alone. Plasma osmolality and arginine vasopressin levels were not different during 3% saline infusions with and without AII or with phenylephrine. Thus, a minimally pressor infusion of AII significantly potentiated the response of mean arterial pressure to hypertonic volume expansion in healthy humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological arginine vasopressin levels do not enhance baroreflex function in normal humans.

Physiological increases in arginine vasopressin (AVP) have been shown to potentiate baroreflex activity in experimental animals. Pharmacological amounts of AVP have been shown to decrease sympathetic nervous system activity in humans, whereas the role of smaller increases in plasma AVP is unclear, either for baroreflex function or sympathetic activity. The present study tested the hypotheses that in normal humans physiological increases in plasma AVP would 1) decrease basal sympathetic nervous system activity as measured by systemic venous norepinephrine (NE) spillover; 2) enhance or restrain the increases in heart rate (HR), forearm vascular resistance, and NE spillover during baroreceptor unloading during head-up tilt; and 3) augment the decline in HR and NE spillover during baroreceptor loading with head-down tilt and/or with phenylephrine infusion plus head-down tilt. In the baroreceptor unloading studies, HR, arterial pressure, forearm blood flow, plasma NE, NE clearance, and NE spillover were assessed during infusions of AVP (plasma AVP 16-20 pg/ml) or vehicle (given double blind) in the supine position. All variables then were assessed during 15 min of head-up tilt. In the baroreflex loading studies, the same assessments (except forearm blood flow) were made during 15 min of head-down tilt followed by 15 min of head-down tilt plus phenylephrine. Compared with vehicle, AVP had no effect on the responses of any variable in the supine position or on the expected reflex responses during head-up tilt and head-down tilt plus phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of angiotensin II on noradrenaline release in the human forearm.

OBJECTIVE: The aim was to test the hypothesis that in normal humans angiotensin II would stimulate local release of noradrenaline under basal conditions or during a sympathetic stimulus provided by lower body negative pressure (LBNP). METHODS: Nine healthy volunteers received intra-arterial infusions of angiotensin II, 5 ng.min-1, into the non-dominant forearm. Forearm blood flow (strain gauge plethysmography) and regional noradrenaline spillover (using the tracer methodology of Esler) were measured during angiotensin II alone, LBNP alone, and LBNP plus angiotensin II. RESULTS: Angiotensin II and LBNP decreased forearm blood flow comparably: from 3.1(SD 1.5) to 2.4 (0.9) ml.100 g-1.min-1 during angiotensin II, p < 0.05; and from 3.3(1.5) to 2.5(1.0) ml.100 g-1.min-1 during LBNP, p < 0.05 (p = NS, A-II v LBNP). Angiotensin II had no effect on forearm venous noradrenaline or regional noradrenaline spillover. LBNP increased venous noradrenaline outflow from the forearm, from 1.6(0.40) to 2.1(0.6) nmol.min-1 (p < 0.05), while regional noradrenaline spillover tended to increase, rising from 1.5(0.8) to 2.0(1.0) nmol.100 ml-1.min-1. Angiotensin II did not enhance forearm blood flow or noradrenaline responses to LBNP. CONCLUSIONS: In the human forearm, mildly vasoconstrictor infusions of angiotensin II do not increase local release of noradrenaline, either alone or during mild LBNP. At least under these conditions, angiotensin II would not appear to be a potent influence on local sympathetic activity.