Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria.

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.

Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial.

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.

Laboratory processing and intracytoplasmic sperm injection using epididymal and testicular spermatozoa: what can be done to improve outcomes?

There are two main reasons why sperm may be absent from semen. Obstructive azoospermia is the result of a blockage in the male reproductive tract; in this case, sperm are produced in the testicle but are trapped in the epididymis. Non-obstructive azoospermia is the result of severely impaired or non-existent sperm production. There are three different sperm-harvesting procedures that obstructive azoospermic males can undergo, namely MESA (microsurgical epididymal sperm aspiration), PESA (percutaneous epididymal sperm aspiration), and TESA (testicular sperm aspiration). These three procedures are performed by fine-gauge needle aspiration of epididymal fluid that is examined by an embryologist. Additionally, one technique, called TESE (testicular sperm extraction), is offered for males with non-obstructive azoospermia. In this procedure, a urologist extracts a piece of tissue from the testis. Then, an embryologist minces the tissue and uses a microscope to locate sperm. Finding sperm in the testicular tissue can be a laborious 2- to 3-hour process depending on the degree of sperm production and the etiology of testicular failure. Sperm are freed from within the seminiferous tubules and then dissected from the surrounding testicular tissue. It is specifically these situations that require advanced reproductive techniques, such as ICSI, to establish a pregnancy. This review describes eight different lab processing techniques that an embryologist can use to harvest sperm. Additionally, sperm cryopreservation, which allows patients to undergo multiple ICSI cycles without the need for additional surgeries, will also be discussed.

Laboratory processing and intracytoplasmic sperm injection using epididymal and testicular spermatozoa: what can be done to improve outcomes?

There are two main reasons why sperm may be absent from semen. Obstructive azoospermia is the result of a blockage in the male reproductive tract; in this case, sperm are produced in the testicle but are trapped in the epididymis. Non-obstructive azoospermia is the result of severely impaired or non-existent sperm production. There are three different sperm-harvesting procedures that obstructive azoospermic males can undergo, namely MESA (microsurgical epididymal sperm aspiration), PESA (percutaneous epididymal sperm aspiration), and TESA (testicular sperm aspiration). These three procedures are performed by fine-gauge needle aspiration of epididymal fluid that is examined by an embryologist. Additionally, one technique, called TESE (testicular sperm extraction), is offered for males with non-obstructive azoospermia. In this procedure, a urologist extracts a piece of tissue from the testis. Then, an embryologist minces the tissue and uses a microscope to locate sperm. Finding sperm in the testicular tissue can be a laborious 2- to 3-hour process depending on the degree of sperm production and the etiology of testicular failure. Sperm are freed from within the seminiferous tubules and then dissected from the surrounding testicular tissue. It is specifically these situations that require advanced reproductive techniques, such as ICSI, to establish a pregnancy. This review describes eight different lab processing techniques that an embryologist can use to harvest sperm. Additionally, sperm cryopreservation, which allows patients to undergo multiple ICSI cycles without the need for additional surgeries, will also be discussed.

Uterine cavity findings and hysteroscopic interventions in patients undergoing in vitro fertilization-embryo transfer who repeatedly cannot conceive.

OBJECTIVE: To assess hysteroscopic findings in patients undergoing IVF-ET who repeatedly failed to conceive despite transfer of good-quality embryos. DESIGN: Prospective, observational study. SETTING: Clinical research unit for reproductive medicine in a private clinic. PATIENT(S): Fifty-five patients with a normal uterine cavity on hysterosalpingography before the initial IVF-ET cycle and two previous failed IVF-ET attempts despite transfer of a minimum of two good-quality embryos on each occasion. INTERVENTION(S): Standard transvaginal ultrasonography and diagnostic and therapeutic hysteroscopy. MAIN OUTCOME MEASURE(S): Endometrial findings on transvaginal ultrasonography and hysteroscopy and outcome of the cycles after surgical hysteroscopy and antibiotic therapy. RESULT(S): Twenty-five (45%) patients had abnormal endometrial findings and underwent treatment to correct the lesions. All patients underwent a third IVF-ET cycle. Pregnancy (50% vs. 20%) and implantation (19% vs. 5.5%) rates were significantly higher in patients who were treated for uterine abnormalities than in patients who had normal uterine cavities on hysteroscopy. CONCLUSION(S): The incidence of pathologic findings on hysteroscopy is high in patients with repeated failures of IVF-ET. Evaluation of endometrial integrity by hysteroscopy is highly valuable and should be applied to all such cases.

Pronuclear morphology evaluation with subsequent evaluation of embryo morphology significantly increases implantation rates.

OBJECTIVE: To elucidate the relative predictive value of implantation markers at different stages of preimplantation development. DESIGN: Correlation of pronuclear morphology with embryo morphology and implantation rates in retrospective and prospective analysis of in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) treatment cycles. SETTING: Private infertility center. PATIENT(S): A total of 441 couples undergoing infertility treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Size of pronuclei and distance between them, the number and polarization of nucleolus precursor bodies (NPB) at the one-cell stage, embryo cleavage and fragmentation rates on days 2 and 3, and pregnancy and implantation rates. RESULT(S): Polarization of the NPB in both pronuclei had a statistically significant correlation with normal membrane breakage during ICSI (40%, compared with 33% easy, and 31% difficult membrane breakage) and also with faster cleavage and lower fragmentation rates of embryos. Sixty-one percent of implanting embryos had polarization of the NPB in both pronuclei compared with 37% for all embryos. Larger distance between pronuclei and their unequal size had a statistically significant correlation with slower cleavage and inferior embryo quality. Embryo selection based on only pronuclear morphology or on only day-3 embryo morphology yielded implantation rates of 15.1% and 12.1%, respectively. Embryo selection based on sequential evaluation of both pronuclear morphology and embryo morphology on day 3 resulted in a 21.1% implantation rate. CONCLUSION(S): Polarization of NPB in both pronuclei is as reliable marker of implantation as embryo morphology on day 3. However, pronuclear morphology assessment improves embryo selection only when it is combined with embryo morphology evaluation on day 3.

Novel use of laser to assist ICSI for patients with fragile oocytes: a case report.

An inadvertent consequence of intracytoplasmic sperm injection (ICSI) is the degeneration of some of the microinjected oocytes. Most patients may not suffer any disadvantage through losing oocyte(s) during micromanipulation; however, in some circumstances, this can result in a reduction of the chances for pregnancy. This study reports a clinical pregnancy obtained by a novel approach using laser-assisted micro-opening of the zona pellucida prior to ICSI to secure a non-traumatic microinjection that avoids degeneration of oocytes. A total of 12 oocytes were obtained from the 36 year old patient in her third IVF treatment cycle, following two previously failed attempts where very high degeneration rates of oocytes after ICSI were recorded, together with suboptimal embryo quality. Five of the 11 matured (MII) oocytes were submitted to conventional ICSI and the other six MII oocytes first underwent laser-assisted opening of the zona pellucida (5-7 microm hole size was created with a 1.48 microm diode laser) before microinjection (LA-ICSI). Three of the five conventionally microinjected oocytes degenerated while one oocyte fertilized normally and developed to a good quality embryo. After the LA-ICSI procedure, one of the six oocytes degenerated and four oocytes fertilized normally; of these, two developed to excellent quality embryos, one to a good quality embryo and one to a poor quality embryo. The three best embryos (LA-ICSI group) were transferred to the patient on day 3. Rising serum human chorionic gonadotrophin concentrations were measured 12 days after transfer and on week 7 two implantation sites were detected, together with regular heart activity. The results of the present report suggest that laser-assisted ICSI may provide a safer approach to non-traumatic microinjection of oocytes than conventional ICSI, thereby minimizing the risk of degeneration and possibly also improving embryo quality. Therefore, it is suggested that laser-assisted ICSI might be applied in all cases associated with difficult zona pellucida penetration or/and fragile oolemma, or where patients have very few oocytes available, to improve the chances for pregnancy.

Heterotopic triplet pregnancy: report and video of a case of a ruptured tubal implantation with living embryo concurrent with an intrauterine twin gestation.

This report presents a case of triplet heterotopic gestation after intracytoplasmic sperm injection (ICSI)-IVF treatment, with a left ruptured ectopic tubal implantation with a living embryo and successful outcome of the concurrent intrauterine twin gestation. A couple whose infertility was caused by oligoasthenozoospermia was referred for ICSI treatment. Three good quality embryos were transferred at the request of the patient. Early gestational control was performed by ultrasound at weeks 5 and 7 of gestation. The patient reported to the centre during week 7 with severe abdominal pain and with signs of peritoneal irritation. Transvaginal ultrasound revealed an extra-uterine ruptured implantantion. During the concomitantly performed laparoscopic procedure, a living embryo was observed after opening the extra-uterine embryonic sac. Heartbeat activity was present and lasted for 5 min after surgical resection of the tubal implantation. The patient was discharged from hospital without complications. The intrauterine twin gestation was not affected and two healthy infants were born at week 38 of gestation. Heterotopic pregnancy should be ruled out in patients submitted to IVF-embryo transfer, although no predisposing factors are present in some cases. Precise diagnosis may be delayed due to some important characteristics of the IVF-embryo transfer treatment. Nevertheless, this condition should be diagnosed by ultrasound before tubal rupture to avoid obvious complications. Laparoscopy remains the gold standard for diagnosis and treatment in these cases. The presentation of the heterotopic pregnancy was recorded on video and may be viewed on the internet at www.rbmonline.com/Article/710.

Relationship between time period after vasectomy and the reproductive capacity of sperm obtained by epididymal aspiration.

BACKGROUND: It is not well defined whether the elapsed time after vasectomy has any influence on the outcome of IVF-ICSI using epididymal sperm. We analysed retrospectively the results of 151 ICSI cycles in which sperm of vasectomized men were used at different time periods after vasectomy. METHODS: Oocytes were obtained after a desensitizing ovarian stimulation protocol using GnRH agonist in association with recombinant FSH and HCG. Sperm were retrieved by percutaneous epididymal sperm aspiration. The cycles were split into three groups: < or =10 years after vasectomy (group 1, n = 47), 11-19 years after vasectomy (group 2, n = 79), and > or =20 years after vasectomy (group 3, n = 25). RESULTS: As might be expected, the mean age of men differed in the three groups (group 3 > group 2 > group 1), and the mean age of the women was also significantly higher in group 3 than in groups 1 and 2, although no differences were described between groups 2 and 3. All other laboratory and clinical parameters were similar in the three groups. Ongoing pregnancy and implantation rates (34, 25, 8% and 22, 15, 6% respectively) decreased significantly from group 1 to group 3. CONCLUSION: Pregnancy and implantation rates after ICSI with sperm from vasectomized men are negatively correlated with the time interval from vasectomy, which cannot be explained purely by male or female ageing.

ICSI and day 5 embryo transfers: higher implantation rates and lower rate of multiple pregnancy with prolonged culture.

This retrospective review study, carried out in a private IVF clinic, compared pregnancy and implantation rates with day 3 versus day 5 embryo transfers in a selected group of patients. Participants were patients who failed to achieve pregnancy in at least one previous attempt with embryo transfer on days 2 or 3, and had more than five oocytes fertilized. A total of 296 patients who had undergone day 3 (group A) transfers were compared with 154 who had undergone day 5 transfers (group B). Interventions were intracytoplasmic sperm injection (ICSI), day 3 and day 5 embryo transfer. Outcome measures were pregnancy, implantation, multiple gestation and blastocyst formation rates. Overall, 86.4% of embryos were at the six- to eight-cell stage at 72 h and 30% developed to blastocyst by day 5. The mean number of embryos transferred was 4.0 on day 3 and 3.0 on day 5. Pregnancy and implantation rates were 34.8 and 11.5% in group A, versus 45.3 and 18.5% in group B. Multiple gestation rate was 47.1% in group A and 28.5% in group B. Prolonging embryo culture in vitro to day 5 improved embryo selection and implantation rates. A significant decrease in high order gestations was achieved by reducing the number of embryos transferred, without compromising the pregnancy rates.