Category Archives: Stem Cell Medical Center

Roundtable Discussion: Ziari Assesses Therapy Sequencing in … – Targeted Oncology

Mohammadbagher Ziari, MD

Assistant Clinical Professor

Department of Medical Oncology & Therapeutics Research

City of Hope

Corona, CA

CASE SUMMARY

A 70-year-old woman received a diagnosis of stage I multiple myeloma. She had a medical history of stage 3 chronic kidney disease and moderate renal impairment, and fluorescence in situ hybridization testing showed deletion 17p. The patient declined autologous stem cell transplantation and received lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd). Her best response was a very good partial response (VGPR), and lenalidomide maintenance continued.

Two years later she had her first relapse while on lenalidomide maintenance. On routine follow-up, the patient reported having mild fatigue, but continued to work full time. Her bone marrow plasma cells, light chains, and M protein were rising while her kidney function was worsening, and she now has stage IV chronic kidney disease. The patient received daratumumab (Darzalex) plus pomalidomide (Pomalyst) with a best response of VGPR. One year later a second relapse was discovered, and her kidney function continued to decline.

DISCUSSION QUESTIONS

ZIARI: Based on the NCCN [National Comprehensive Cancer Network] guidelines, there are preferred regimens for [patients with] early relapses with 1 to 3 prior treatments. If the patient has a relapse after more than 6 months, the regimen used primarily can be repeated. Patients who are still sensitive to bortezomib and lenalidomide have options that include ixazomib [Ninlaro], lenalidomide, and dexamethasone, which is a category 1 recommendation, and then RVd.

For bortezomib-refractory patients, one can use any of the regimens that have lenalidomide or a combination of daratumumab, carfilzomib [Kyprolis], and dexamethasone. For patients with lenalidomide-refractory disease, you can do daratumumab, carfilzomib, and dexamethasone; or daratumumab, bortezomib, and dexamethasone; or isatuximab [Sarclisa], carfilzomib, and dexamethasone.1

CHALLAGALLA: Most of them are exposed in my practice already. So in this patient, if shes still not going to go to stem cell transplant or CAR [chimeric antigen receptor] T-cell therapy, I think I would go with isatuximab, carfilzomib, and dexamethasone.

SOLANKI: Theres still selinexor [Xpovio] and other drugs. This has become such a chronic disease.

ZIARI: RightI mean, now that your patient has relapsed with Dara-Pd. We have used the anti-CD38, the IMiD, and the PI. The unmet need seems to be a new agent, probably with a different mechanism of action.

BHANDARI: I think this is when we start getting into either sending the patient for some trials at a tertiary center or sending the patient maybe for evaluation for CAR T-cell therapy or another BCMA [B-cell maturation antigen] type of therapy.

DISCUSSION QUESTION

ZIARI: What do you consider? Is there any other MOA that you think we need to address?

ARJUNAN: Yes, I think thats always a thought in my mind when were switching therapies. In this patient, I think you certainly would be looking at switching MOA, so you kind of think about selinexor, elotuzumab [Empliciti], and some of those other drugs out there. The big concern I have, regardless of the MOA, is the tolerance issue. It becomes worrisome trying to get these patients who are a little bit beat up on their first line of therapies onto some of these other ones.

ZIARI: You touched a great point, exactly. We have other regimens that are recommended like bortezomib, liposomal doxorubicin, and dexamethasone or carfilzomib and dexamethasone. There is CyBorD [cyclophosphamide (Cytoxan), bortezomib, dexamethasone]; carfilzomib, cyclophosphamide, and dexamethasone; or ixazomib, cyclophosphamide, and dexamethasone. Also, [we have] selinexor, bortezomib, and dexamethasone, or other selinexor-based regimens such as daratumumab and dexamethasone.

We also have venetoclax (Venclexta) and dexamethasone only in [patients with] t(11;14). Elotuzumab, pomalidomide, and dexamethasone is another option for a patient who had an IMiD [immunomodulatory drug] and PI [proteasome inhibitor] and progressed within 60 days of completion of last treatment. Pomalidomide and dexamethasone is category 1, and selinexor, pomalidomide, and dexamethasone is another option. There are other older regimens like DCEP [dexamethasone, cyclophosphamide, etoposide (Toposar), cisplatin (Platinol)].1 I dont know if any of you have used it recently, but I know that a long time ago I used it, but not anymore.

DISCUSSION QUESTIONS

ZIARI: You have used RVd and the patient was on maintenance lenalidomide and then progressed in 2021 [after 2 years]. After the first relapse, the patient was on Dara-Pd and now that you have utilized those MOAs that we talked about, it comes to the second relapse. Now you have options like an XPO1 inhibitor and CAR T-cell therapy, an anti-BCMA, or others. We have used a PI, anti-CD38, and IMiD.

MAZHARUDDIN: Well one thought that comes to mind is that the patient seems to have been off the bortezomib when they progressed. So it kind of opens the potential of reintroducing a proteasome inhibitor.

CHALLAGALLA: I agree with that. I think I would use carfilzomib, selinexor, and dexamethasone.

ZIARI: Would you do selinexor, bortezomib, and dexamethasone?

CHALLAGALLA: [This patient] doesnt have any history of cardiomyopathy or CHF [congestive heart failure]. Id like to avoid neuropathy. I would still try to push her toward stem cell transplant or CAR T-cell therapy because she does not seem to be refractory but is just relapsing.

SOLANKI: In the BOSTON trial [NCT03110562], most of the patients had been exposed to multiple agents. But they reintroduced bortezomib in those patients, and some of them got it within the last 6 to 9 months or less than 1 year, and they still showed a response. In fact, in the [bortezomib and dexamethasone] arm of the study, there was a response to bortezomib.2 So if [this patient] is otherwise suitableI dont know what her creatinine clearance is, was it good enough for CAR T-cell therapy?

ZIARI: Yes, youre correct.

DISCUSSION QUESTION

ZIARI: There is the genetic risk, like deletion 17p. Also, patient comorbidities like renal impairment and hypertension, or prior toxicities such as neuropathy. Is neuropathy something that you see in your patient after you use triple regimen for 2 lines of therapy? Is it something that you see despite using subcutaneous proteasome inhibitors? Is this something that is a challenge in your practice?

KANNAN: Its concerning. I think it affects their quality of life because its a chronic disease. Most of my patients develop it with bortezomib-based therapy at first-line therapy, so it tends to be a major problem.

ZIARI: What do you think, Dr Kannan, about the regimen that you would choose for your patient who had 2 lines of triple treatment in the past and now youre going to third-line therapy? What would you use?

KANNAN: Sometimes Ive done carfilzomib-based therapy because theyve had RVd followed by Dara-Pd. Ive tried selinexor. I push them toward CAR T-cell therapy, obviously if they are not refractory, but I still dont understand why this patient did not have a bone marrow transplant. Or did they have a transplant in between? If they have not had a transplant, they should be considered for transplant with the option of CAR T-cell therapy for the future, but I would collaborate with my [transplant physician] for them.

ZIARI: How far [away] is the transplant or CAR T-cell therapy center?

KANNAN: 20 miles.

ZIARI: I see; not bad, not bad at all. The MOA is important, too, if your patient has progressed on a treatment. If you use something new, think of the safety, exactly as you mentioned about neuropathy and different safety issues. We want to just use something that will not only keep the longevity but also the quality of life the same as much as we can. Always consider cost to the patient too: how much is out of their pocket and the distance theyre dealing with. I dont know how much geography is a problem when it comes to using oral regimen vs not oral regimen. Is it something concerning if the patient lives far away from you?

KANNAN: I dont think distance is a problem, but cost can be a major problem in our patient population, which is a little bit lower socioeconomically, and that affects [adherence].

ZIARI: That is true in every single practice, and you feel it more in the community practice.

CASE UPDATE

The patient was started on selinexor plus Vd based on her worsening renal impairment, deletion 17p status, and prior therapies. She achieved a VGPR.

DISCUSSION QUESTIONS

ARJUNAN: Ive used it once. We ran out of options for the patient. I was working in conjunction with [The University of Texas] MD Anderson [Cancer Center]. It was tough. A lot of fatigue, diarrhea as well, and it was quite a lot of monitoring.

ZIARI: Did you use it after multiple lines orin combination with bortezomib or anything else?

ARJUNAN: I used it after multiple lines.

ZIARI: You used it as a doublet treatment with dexamethasone or with bortezomib?

ARJUNAN: Yes, a doublet treatment with dexamethasone.

CHALLAGALLA: Ive used it as a doublet treatment, too, in an elderly person with terrible neuropathy. The indication was triplet therapy with bortezomib, but there was no way I could use bortezomib, so I did the 80-mg selinexor with dexamethasone.

I mean, its a different mechanism, except you must watch out for hyponatremia in this older population from the nausea, vomiting, and diarrhea, and I think we are all pretty good with the hematologic toxicities. We are pretty good at treating them. I think its the neurologic toxicity and the hyponatremia that we need to be careful of.

ZIARI: I have the same experience that you both had before. Just the hyponatremia is something to monitor closely, and fatigue too.

ZIARI: The BOSTON study data showed the efficacy and the adverse effects [AEs] of selinexor. Some of you have experience with it and some of you dont. But based on the data, how would you discuss this with your patient?

BHANDARI: Were there any patients on dialysis on that study?

ZIARI: They included patients who had kidney function less than 40%,2 so patients on dialysis [were] included.

ARJUNAN: Yes, so I think its a discussion about the data, to some extent. What concerns me about these data is that [the study] used, in my opinion, kind of a comparator arm that was questionable. About 70% of the patients had prior exposure to bortezomib already and then theyre using that as a comparator arm, so its kind of like youre expecting that comparator arm to fail, basically. I dont see what the data show me beyond telling the patient, Hey, maybe let us add selinexor, which has a different mechanism of action. It might help you. But I think when were looking at the data, its hard to use that as a convincing reason.

I dont know if there was, perhaps, a better comparator arm that could have been used in this trial instead of Vd alone. But otherwise, its about discussing the AEs and just counseling [the patients] through that. It is kind of difficult because with the other options you might have other toxicities. [As with] belantamab [Blenrep], you have the ophthalmic toxicity. So its weighing what the patient would be tolerant to.

ZIARI: I think there are data that we have also that compared pomalidomide, bortezomib, and dexamethasone with Vd. Also, they did a similar [study] but with Dara-Vd vs Vd and looked at the PFS [progression-free survival] difference too. I guess for the data that we have, the control arm was the old regimen that in the past had been a standard. Thats the reason that they always have something in addition to the doublet, with a different MOA to see if it is better than the standard.

DISCUSSION QUESTIONS

CHALLAGALLA: We always dose reduce. Nausea/vomiting is easily controlled, but we dose reduce if there [will] be AEs.

ZIARI: For the dose that we reduce to, there are data about that dose, so that you dont lose the efficacy. Have you used olanzapine [as an antiemetic]?

CHALLAGALLA: Thats the problem I have with all these drugs. There is no drop in efficacy by dose reduction, so why do we have to use the full dose and make the patient suffer?

ZIARI: In the BOSTON study, most patients had [dose modifications] eventually. You can always lower the dose too. This is what weve learnedthat maybe a lower dose is not a problem. I mean, again, in the BOSTON study, eventually they had most patients on the 80-mg dose.

SOLANKI: This question came up way back when panobinostat [Farydak] was introduced. It clearly disappeared mainly because it had severe GI [gastrointestinal] toxicity, mainly diarrhea. This has been a recurring problem with drugs, like now with selinexor. What Dr Challagalla pointed out is a recurring theme. We say, Oh well, 70% of the patients had to have dose reductions. Well, how did we come up with this dose in the first place?

The same thing happened with bortezomib way back. We used to use much higher doses, and then we went to weekly dosing. It turns out that the total dose of bortezomib we give is considerably less than what was originally used, and we still see wonderful responses. So theres a significant issue with the starting dose that is used in trials. Nobody seems to report what was the delivered dosehow much did the patient get, not what was planned.

ZIARI: In the BOSTON study they did. The majority [of patients received] 80 mg.

SOLANKI: I think what happened with the BOSTON [From the Data2] trial was because of the design, it became a once-a-week regimen of selinexor, and that considerably decreased the GI toxicity. Still, there was considerable dose reduction in those patients. So its still a pretty tough drug, although I was surprised how effective the combination was in patients who were penta refractory. Even in the Vd arm, there was a response rate of about 35% or 30% which is remarkable, so it was an interesting study, but not an easy one on the patients.

ZIARI: I have patients on this and I have been dose reducing, even down to 40 mg and they still have a response to it. I have 2 patients currently on it and down to 40 mg once a week, and I see the efficacy. I had to dose reduce to different things. But one other thing I do is olanzapine on day 1 of the treatment, and then I do it for 3 days in a row. I ask the patient how they feel after 3 days. If theyre fine, then I just ask them to use it as needed. If you do it days 1 to 3, and 1 hour before the starting day, then continue for 3 days or use a different cocktail plus hydration, it pretty much gets easier. Typically, after the first 2 months, the patient tolerates it and the AEs get less and less.3

DISCUSSION QUESTION

CHALLAGALLA: My choice would depend on the comorbidities of the patient. If the patient has severe neuropathy, bortezomib is out. Cardiomyopathy, carfilzomib is out, or kidney disease too. If theyve been exposed to daratumumab, I dont think I would use any anti-CD38 drug again because I dont believe that reusing it is going to be helpful. I dont know whats the right answer. It depends on the patient. In my practice, if I have used RVd and then daratumumab, etc, then XKd [selinexor, carfilzomib, and dexamethasone] seems most reasonable because if the same patient had kidney disease, I would have probably used pomalidomide before.

ZIARI: I see. So if you want to use a combination with selinexor, where do you think it fits in your line of treatment?

CHALLAGALLA: One can use selinexor and dexamethasone. One could use anything. We have so many choices right now, and we must weigh the AEs and patients comorbidities, then choose. Thats the way I would think.

ZIARI: Thats correct. We have great choices available now, but youre talking about a different MOA when you use selinexor. Weve pretty much run out of many other MOAs, and we were thinking about something new.

REFERENCES

NCCN. Clinical Practice Guideline in Oncology. Multiple Myeloma, version 1.2023. Accessed February 22, 2023. https://bit.ly/3KqmxUF

Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3

Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed February 22, 2023. https://bit.ly/3eG0OqV

Continued here:
Roundtable Discussion: Ziari Assesses Therapy Sequencing in ... - Targeted Oncology

FDA Fast Tracks BCMA-Targeted CAR T-Cell Therapy for R/R … – AJMC.com Managed Markets Network

A version of this article was originally published on OncLive. This version has been lightly edited.

The FDA has granted a fast track designation to CB-011, a CRISPR-edited allogeneic chimeric antigen receptor (CAR) T-cell therapy developed by Caribou Biosciences, for the treatment of patients with relapsed/refractory multiple myeloma.1

CB-011 targets the B-cell maturation antigen (BCMA). This is the first allogeneic anti-BCMA CAR T-cell therapy engineered to improve duration of antitumor response through an immune cloaking, genome-editing approach that removes the B2M protein and inserts a B2MHLA-E fusion protein, according to the company.2

In November 2022, the FDA cleared an Investigational New Drug application for CB-011.2 Now, the product is under evaluation in the multicenter, open-label study CaMMouflage trial (NCT05722418).3,4

Fast Track designation for CB-011 allows us instrumental interactions with the FDA as we progress our clinical development and regulatory plans for CB-011, Syed Rizvi, MD, chief medical officer at Caribou Biosciences, stated in a press release.1 This designation could not be [timelier,] as we recently dosed our first patient in the phase 1 CaMMouflage trial.

The CaMMouflage trial will include patients who have received at least 3 prior lines of therapy. Eligible patients are also required to have an ECOG performance status of 0 or 1 and to have adequate hematologic, renal, hepatic, pulmonary, and cardiac function.3

Patients who have received a BCMA-targeted therapy within 3 months of enrollment and/or any prior CAR T-cell therapy are excluded. Those who received autologous stem cell transplant within 6 weeks of lymphodepletion or allogeneic stem cell transplant within 6 months of lymphodepletion, who have an active or prior history of central nervous system involvement, or who have received a live, attenuated vaccine with 4 weeks of lymphodepletion are not eligible.3

In the part A, the escalation stage of the trial, investigators will assess ascending doses of CB-011 in combination with cyclophosphamide and fludarabine to establish the recommended phase 2 dose (RP2D) of the regimen in a standard 3+3 dose-escalation design. For part B, the expansion stage, investigators will assess responses to the RP2D, or the maximum tolerated dose as measured by International Myeloma Working Group criteria.3

Recruitment for CaMMouflage is ongoing. Caribou shared plans to assign patients to a single administration of CB-011 at a dose of 50 x 106 CAR T cells this year.1

Cas12a CRISPR hybrid RNA-DNA (chRDNA) technology was utilized to make 4 gene edits in the creation of CB-011. In edits 1 and 2, investigators target cancer cells by site-specifically inserting a humanized anti-BCMA CAR into the TRAC gene. This mechanism knocks out T cell receptor expression, thereby reducing the risk for graft-vs-host disease (GVHD).2

In edits 3 and 4, investigators prevent recognition and rejection by patient T cells and blunt rejection by natural killer (NK) cells by site-specifically inserting a B2MHLA-E peptide fusion gene into the B2M gene of the CAR T cells. These edits disable endogenous B2M expression, which eliminates endogenous HLA class I presentation and reduces T cell-mediated rejection. At the same time, these changes facilitate expression of B2MHLA-E which reduces rejection caused by NK cells.2

Prior preclinical findings presented at the 2022 AACR Annual Meeting indicated that the CAR T cells expressing the B2M-HLA-E fusion induced a survival benefit compared with cells that do not express the fusion in the presence of NK cells in vitro.4 This result suggests that these cells may be able to fight off a recipients NK cells and circulate longer.

Furthermore, CB-011 induced long-term survival in mice carrying established orthotopically-engrafted multiple myeloma cells. Mice who received high doses of CB-011 also appeared to avoid GVHD.4

Our goal is to develop CB-011 as a readily available off-the-shelf treatment option for patients with relapsed or refractory multiple myeloma to overcome the need for apheresis or bridging therapy, variable quality and long manufacturing timelines, manufacturing failures, or the inability to bear the burden of treatments that require frequent dosing over several months, Rizvi added in the press release.1

CB-011 is Caribous second allogeneic CAR T-cell agent that is under exploration in hematologic malignancies.

Investigators are assessing CB-010, a CAR T-cell therapy with a PD-1 knockout, in patients with relapsed or refractory B cell non-Hodgkin lymphoma as part of the ongoing phase 1 ANTLER trial NCT04637763).2 One patient in that trial who received 8 prior lines of systemic therapy had an ongoing complete response through month 15.5

References

1. Caribou Biosciences announces FDA granted fast track designation to CB-011, an allogeneic CAR-T cell therapy for relapsed or refractory multiple myeloma. News release. Caribou Biosciences. April 4, 2023. Accessed April 6, 2023. https://investor.cariboubio.com/

2. Caribou Biosciences announces FDA clearance of IND application for CB-011, an allogeneic anti-BCMA CAR-T Cell therapy for the treatment of relapsed or refractory multiple myeloma. News release. Caribou Biosciences. November 21, 2022. Accessed April 6, 2023. https://investor.cariboubio.com/news-releases/

3. CRISPR-edited allogeneic anti-BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma (CaMMouflage). Updated March 2, 10, 2023. Accessed April 6, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05722418

4. Garner E, Degagne E, Roy S, et al. A BCMA-specific allogeneic CAR-T cell therapy (CB-011) genome-engineered to express an HLA-E fusion transgene to prevent immune cell rejection. Cancer Res. 2022;82(suppl 12):LB009. doi:10.1158/1538-7445.AM2022-LB009

5. CRISPR-edited allogeneic anti-CD19 CAR-t cell therapy with PD-1 knockout induces prolonged complete response in relapsed/refractory follicular lymphoma patient: case report from CB-010 ANTLER trial. Presented at: the Lymphoma, Leukemia, & Myeloma Congress; New York, NY; October 18-22, 2022.

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FDA Fast Tracks BCMA-Targeted CAR T-Cell Therapy for R/R ... - AJMC.com Managed Markets Network

Bazedoxifene and cholecalciferol | DDDT – Dove Medical Press

Introduction

Osteoporosis is a skeletal disorder characterized by low bone mass and an increased risk of bone fracture. Bone mass reaches its peak in young adulthood, and increased bone resorption relative to bone formation leads to the lowering of bone mass. According to the World Health Organization, osteoporosis is defined as hip or lumbar spine bone marrow density of more than 2.5 standard deviations below the mean found in the young-adult population.1 Osteoporosis is a significant public health concern among the elderly due to the increased morbidity and mortality associated with bone fractures. It affects both sexes and all races, and its prevalence is expected to rise as the global population continues to age.1

The pharmacologic agents for the prevention and treatment of osteoporosis include calcium, vitamin D, bisphosphonates, calcitonin, estrogen, selective estrogen receptor modulator (SERM), parathyroid hormone, and anti-receptor activator of nuclear factor-kappa B ligandantibody (denosumab).2 The therapeutic potential of new treatment approaches, such as exosomes derived from endothelial cells or mesenchymal stem cells, has been investigated recently in animal models.3,4

Bazedoxifene, a third-generation SERM, exhibits tissue-selective action, functioning as an agonist in skeletal tissue but as an antagonist in breast and uterine tissues.5,6 Bazedoxifene has been approved for the treatment of postmenopausal osteoporosis by the European Medicines Agency, and conjugated estrogens/bazedoxifene have been approved for the prevention of postmenopausal osteoporosis by the United States Food and Drug Administration.7,8 Cholecalciferol, commonly known as vitamin D3, plays an important role in bone metabolism. Cholecalciferol is converted to calcifediol (25-hydroxycholecalciferol) in the liver and then to calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, in the kidney. Although vitamin D can be obtained from dietary intake and synthesized in the skin after exposure to sunlight, its deficiency is common. The National Osteoporosis Foundation recommends 8001000 IU of vitamin D intake per day for individuals aged 50 and older.1

A fixed-dose combination formulation of bazedoxifene and cholecalciferol is a potentially promising therapeutic option for postmenopausal osteoporosis patients as it can improve treatment efficacy and medication compliance. Before developing a fixed-dose combination formulation, the pharmacokinetic (PK) interactions between bazedoxifene and cholecalciferol need to be assessed. This study aimed to examine the PK interactions between these drugs as well as their safety and tolerability when co-administered in healthy male subjects.

The study was designed as an open-label, randomized, three-period, three-treatment, six-sequence, crossover clinical trial. Healthy male volunteers aged between 19 and 40 years with body mass index (BMI) between 19 and 28 kg/m2 were eligible for inclusion. Subjects were screened based on past medical history, physical examination including vital signs (blood pressure, heart rate, and body temperature), urine drug screening, clinical laboratory tests, serology tests, and 12-lead electrocardiogram (ECG). Subjects with a history of venous thromboembolism, hypercalciuria, renal stone, hepatobiliary disease, galactose intolerance, drug abuse, or clinically significant hypersensitivity reaction were excluded.

A total of 30 subjects were randomly assigned to six sequences comprised of three treatments: one tablet of 20 mg bazedoxifene (Viviant; Pfizer Ltd., Seoul, Korea), two tablets of 800 IU cholecalciferol (HGP1501; Hanmi Pharmaceutical Co. Ltd., Seoul, Korea), or one tablet of 20 mg bazedoxifene along with two tablets of 800 IU cholecalciferol (Table 1). Outpatient visits were scheduled on day 10 of period 1 and day 9 of periods 2 and 3. At that time, subjects were provided with sunscreens (sun protection factor 50) and diaries to record their diet and activity. Subjects were asked to limit their exposure to sunlight by applying sunscreen and covering themselves with clothes and hats for outdoor activities. Subjects were required to refrain from taking dietary supplements and foods high in vitamin D content. Between two consecutive periods, there was a washout period of at least 14 days. These subjects were admitted to the Clinical Trial Center at Asan Medical Center (Seoul, Korea) the day before drug administration. The test drugs were administered orally under fasting conditions with 150 mL of water. After receiving the investigational drug(s), subjects were required to fast for four hours. Depending on the treatment, subjects were discharged on either day 2 (bazedoxifene monotherapy) or day 6 (cholecalciferol monotherapy or combined therapy). A follow-up visit was scheduled two weeks after the last dose.

Table 1 Overall Study Design

To determine the plasma bazedoxifene concentration, serial blood samples were collected at 0 (pre-dose), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours after the dosing. To measure the baseline cholecalciferol level, blood samples were collected at 16, 12, 8, and 0 hours before the cholecalciferol dosing, and the average concentration for each individual was used as the baseline cholecalciferol concentration. Baseline-adjusted cholecalciferol concentrations were obtained by subtracting the baseline from the post-dose plasma cholecalciferol concentrations measured at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 48, 72, 96 and 120 hours after the treatment. If the baseline-adjusted cholecalciferol concentration had a negative value, zero was assigned.

Blood samples used for the drug concentration measurements were drawn into ethylenediaminetetraacetic acid K2 tubes. Plasma was separated by centrifugation at 1800 g for 8 minutes at 4 C and stored in Eppendorf tubes at 70 C until analysis. At the analytical laboratory (BioCore Co. Ltd., Seoul, Korea), samples were thawed at room temperature. The plasma concentrations of bazedoxifene and cholecalciferol were assayed using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS). Bazedoxifene samples were prepared by liquid-liquid extraction, and cholecalciferol samples by protein precipitation and solid-phase extraction. Liquid chromatography was conducted using a Shimadzu UFLC system (Shimadzu Corp., Kyoto, Japan). For tandem mass spectrometry, a SCIEX TQ5500 mass spectrometer (AB Sciex LLC, MA, USA) was used. The calibration curves covered the ranges of 0.120 ng/mL for bazedoxifene and 0.110 ng/mL for cholecalciferol. For bazedoxifene, the accuracy of LC-MS/MS was 91.8113.0%, and the precision was 0.15.5%. For cholecalciferol, the accuracy of LC-MS/MS was 92.7105.6%, and the precision was 0.24.5%. The lower limit of quantification was 0.1 ng/mL for both compounds.

The study protocol was approved by the Institutional Review Board (IRB) of Asan Medical Center (IRB number: 20170227) and by the Korean Ministry of Food and Drug Safety. The study was registered at ClinicalTrials.gov (NCT03089112). All subjects provided written informed consent before receiving screening tests. All study procedures were conducted in accordance with the ethical principles stated in the Declaration of Helsinki and by the Good Clinical Practice Guidelines of the International Council for Harmonisation.9,10 The study was conducted from March 31, 2017 to June 16, 2017.

The PK parameters of bazedoxifene and cholecalciferol in each subject were analyzed by the non-compartmental method using Phoenix WinNonlin version 6.4 (Certara, NJ, USA). This analysis was based on the actual sampling time. The maximum plasma concentration (Cmax) and the time to reach Cmax (Tmax) were determined from the observed values. The terminal elimination rate constant (z) was estimated by linear regression analysis of the terminal portion of the semilogarithmic concentration-time curve. The terminal elimination half-life (t1/2) was calculated as the natural log of two divided by z. Demographic data and PK parameters were summarized using descriptive statistics. The Cmax and the values for the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) were log-transformed to compare the drug exposure between the combined therapy and monotherapy. The point estimate and 90% confidence interval (CI) for the geometric mean ratio (GMR) of the combined therapy to monotherapy were obtained for Cmax and AUClast.

Safety and tolerability were assessed throughout the study by physical examinations, laboratory tests (complete blood count, blood chemistry, and urinalysis), 12-lead ECG, and monitoring of adverse events (AEs). AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA version 19.1) and recorded in terms of symptom/sign, onset, duration, severity, relationship to the investigational drug(s), action taken, and outcome.

Of the 30 study participants who received the investigational drug(s) at least once, 27 subjects completed the study (Figure 1). Two subjects withdrew their consent to participate, and one subject was excluded at the investigators discretion due to a medical need for concomitant medication that could potentially affect the PK data. Participant demographics, including age, weight, height, and BMI, are summarized in Table 2. The mean standard deviation (SD) values were 28.63 4.18 years for age, 71.53 6.99 kg for weight, 173.55 4.80 cm for height, and 23.75 2.09 kg/m2 for BMI. All subjects who received the investigational drug(s) at least once were included in the safety and tolerability assessment.

Table 2 Demographic Characteristics of the Participants (n=30)

Figure 1 Subject disposition.

The 27 subjects who completed the study were included in the PK analysis set, and the PK parameters are presented in Table 3. For bazedoxifene, the Cmax values (mean SD) for monotherapy and combined therapy were 3.30 0.92 ng/mL and 3.62 1.39 ng/mL, respectively. The AUClast values (mean SD) for monotherapy and combined therapy were 44.32 22.24 hng/mL and 50.78 24.98 hng/mL, respectively. The mean plasma concentration-time profiles of bazedoxifene for monotherapy and combined therapy nearly overlapped (Figure 2A). For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.92631.1765) for Cmax and 1.1329 (1.02321.2544) for AUClast (Table 4).

Table 3 Pharmacokinetic Parameters of Bazedoxifene and Baseline-Adjusted Cholecalciferol in Healthy Male Subjects (n=27)

Table 4 Geometric Mean Ratios of Combined Therapy to Monotherapy for AUClast and Cmax

Figure 2 Mean plasma concentration-time curves: (A) bazedoxifene (B) baseline-adjusted cholecalciferol. The error bars denote standard deviations.

For baseline-adjusted cholecalciferol, the Cmax values (mean SD) for monotherapy and combined therapy were 2.25 0.47 ng/mL and 1.95 0.54 ng/mL, respectively. The AUClast values (mean SD) for monotherapy and combined therapy were 59.43 22.95 hng/mL and 49.18 24.40 hng/mL, respectively. The mean plasma concentration-time profiles of baseline-adjusted cholecalciferol for monotherapy and combined therapy are shown in Figure 2B. For baseline-adjusted cholecalciferol, the GMR (90% CI) of combined therapy to monotherapy was 0.8543 (0.80050.9117) for Cmax and 0.8056 (0.74450.8717) for AUClast (Table 4).

Seventeen subjects showed a total of 26 AEs after drug administration (Table 5). No serious AE occurred throughout the entire study. All AEs were mild in severity and resolved without any sequelae. The most common AE was nasopharyngitis (five events in five subjects). Clinically significant findings from the physical examination were phlebitis of the arm and venipuncture site bruise. Clinically significant laboratory abnormalities included increased blood levels of creatine phosphokinase and triglyceride and decreased blood levels of neutrophil count. No clinically significant abnormalities were found with respect to vital signs and 12-lead ECG. Twenty-five AEs were considered to have no or unlikely relationship with the investigational drugs. One AE, fatigue observed after combined therapy, was considered to have a possible relationship with the administered drugs.

Table 5 Adverse Events in the Study Population After Drug Administration

This study investigated the PK characteristics of bazedoxifene and cholecalciferol, their PK interactions, and the safety and tolerability of combined therapy with these drugs in healthy male subjects.

The terminal elimination half-life of bazedoxifene was approximately 27 hours, and that of cholecalciferol was 13 hours in our study. The washout period of 14 days should therefore have been sufficient for both investigational drugs to be fully eliminated by the next period. The blood samples obtained up to 120 hours after dosing provided sufficient information for characterizing the exposures to bazedoxifene and cholecalciferol.

Previous studies on bazedoxifene pharmacokinetics have indicated a Tmax of 12 hours and a half-life of approximately 28 hours.11 As shown in Figure 2 and Table 3, bazedoxifene was rapidly absorbed when administered alone or in combination with cholecalciferol, showing median Tmax values of 2.00 h and 1.53 h, respectively. The Tmax of cholecalciferol is known to be approximately 15 hours. In our study, the median Tmax of cholecalciferol was 11.98 h when administered alone, similar to the 12.00 h value found for its co-administration with bazedoxifene.

In a recent study on bazedoxifene, the mean Cmax and AUClast in healthy male subjects after a single 20 mg oral dose were 3.191 ng/mL and 44.697 hng/mL, respectively.12 These numbers are consistent with the results of the current study (3.30 ng/mL and 44.32 hng/mL). The PK parameters Cmax and AUClast were used in our analyses to compare the combined therapy and monotherapy exposures. With bazedoxifene, the 90% CI for the GMR of the combined therapy to bazedoxifene monotherapy for Cmax fell within the 0.801.25 range, and for AUClast it was nearly within the above-mentioned range.

In the case of cholecalciferol, the AUClast was lower when this drug was co-administered with bazedoxifene, as indicated by the GMR of 0.8056 and associated 90% CI of 0.74450.8717. Bazedoxifene and cholecalciferol are drugs that exhibit wide therapeutic ranges.1315 Cholecalciferol is known to reach a sigmoidal dose-response curve plateau at a dose of 600 IU.15 Hence, based on the GMRs observed in our exploratory study, the difference in the AUClast for cholecalciferol is unlikely to have clinical significance in treatment efficacy at the dose level used in our protocol.

All of the AEs observed in our study population were mild, and the frequency of AEs in subjects who received combined therapy was not significantly different from that in subjects who received monotherapy. The most common AE observed in our present trial cohort was nasopharyngitis, which we considered unrelated to the investigational drugs.

One limitation of the present study was that the participants were all healthy men. The study was exploratory in nature, and male subjects were included to facilitate enrollment and minimize health risks to subjects. Drug-drug interaction studies are often conducted with male subjects, and the results are applied to women as well as men because gender does not seem to affect the pattern of drug-drug interaction for many drugs. Assuming that the PK interactions would follow the same pattern in men and women, this study was conducted in men instead of women. Additional studies in postmenopausal women with osteoporosis and patients with different pathophysiological conditions will help further characterize the PK interactions between bazedoxifene and cholecalciferol.

The combined therapy of 20 mg bazedoxifene (one tablet) and 1600 IU cholecalciferol (two tablets of 800 IU) was safe and well tolerated in healthy male subjects. In this present study, the oral co-administration of bazedoxifene with cholecalciferol tended to decrease the cholecalciferol exposure slightly. Considering that both drugs have wide therapeutic ranges, dose adjustment of cholecalciferol may not be necessary for its co-administration with bazedoxifene.

AE, adverse event; AUClast, area under the concentration-time curve from time zero to the last quantifiable concentration; BMI, body mass index; CI, confidence interval; Cmax, maximum plasma concentration; ECG, electrocardiogram; GMR, geometric mean ratio; IRB, Institutional Review Board; LC-MS/MS, liquid chromatography with tandem mass spectrometry; z, terminal elimination rate constant; PK, pharmacokinetic; SD, standard deviation; SERM, selective estrogen receptor modulator; Tmax, time to reach Cmax; t1/2, terminal elimination half-life.

The authors do not intend to share individual de-identified participant data of this study due to confidentiality.

This study was sponsored by Hanmi Pharmaceutical Co. Ltd.

Hyeong-Seok Lim has received grants from Hanmi Pharmaceutical Co. Ltd. for a range of research projects, including the study reported in this article. Jina Jung and Sung Hee Hong are employees of Hanmi Pharmaceutical Co. Ltd. The remaining authors declare no competing interests in relation to this article.

1. Cosman F, de Beur SJ, LeBoff MS, et al. National Osteoporosis Foundation. Clinicians guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):23592381. doi:10.1007/s00198-014-2794-2

2. Rejnmark L, Mosekilde L. New and emerging antiresorptive treatments in osteoporosis. Curr Drug Saf. 2011;6(2):7588. doi:10.2174/157488611795684686

3. Song H, Li X, Zhao Z, et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett. 2019;19(5):30403048. doi:10.1021/acs.nanolett.9b00287

4. Zeng ZL, Xie H. Mesenchymal stem cell-derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review. Biomater Transl. 2022;3(3):175187. doi:10.12336/biomatertransl.2022.03.002

5. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005;146(9):39994008. doi:10.1210/en.2005-0030

6. Stump AL, Kelley KW, Wensel TM. Bazedoxifene: a third-generation selective estrogen receptor modulator for treatment of postmenopausal osteoporosis. Ann Pharmacother. 2007;41(5):833839. doi:10.1345/aph.1H428

7. Conbriza. European medicines agency; 2009. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/conbriza. Accessed October 21, 2022.

8. DUAVEE. Drug Label (NDA 022247). Silver Spring, MD: US Food and Drug Administration; 2013.

9. World Medical Association. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):21912194. doi:10.1001/jama.2013.281053

10. Guideline for Good Clinical Practice E6(R2). International council for harmonisation of technical requirements for pharmaceuticals for human use; 2016. Available from: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed October 21, 2022.

11. Gatti D, Rossini M, Sblendorio I, Lello S. Pharmacokinetic evaluation of bazedoxifene for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol. 2013;9(7):883892. doi:10.1517/17425255.2013.794221

12. Yeun JS, Kan HS, Lee M, et al. Pharmacokinetic comparison of two bazedoxifene acetate 20 mg tablet formulations in healthy Korean male volunteers. Transl Clin Pharmacol. 2020;28(2):102108. doi:10.12793/tcp.2020.28.e7

13. Archer DF, Pinkerton JV, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause. 2009;16(6):11091115. doi:10.1097/gme.0b013e3181a818db

14. Kawate H, Takayanagi R. Efficacy and safety of bazedoxifene for postmenopausal osteoporosis. Clin Interv Aging. 2011;6:151160. doi:10.2147/CIA.S15711

15. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011.

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Bazedoxifene and cholecalciferol | DDDT - Dove Medical Press

Paterson Teacher Dies After Battling Brain Infection, Cancer – Daily Voice

EmilySetteducato has died after battling cancer and a subsequent brain infection on Saturday, April 8, her obituary reads. She was 28 years old.

After battling leukemia, braving multiple rounds of chemotherapy, and receiving a life-saving stem cell transplant from an anonymous donor at just 27 years old, Emily thought her medical woes were over.

The Paterson elementary school teacher had left the hospital, returned to the classroom, celebrated a birthday, and was back to planning a future with her long-time boyfriend, Will.

The future was looking bright for Emily, until she contracted an infection known as the JC Virus, wreaking havoc on her brain.

Emily sister,Jackie Griffin launched a GoFundMe campaignlast January. While Emily was able to undergo treatment atCincinnati Children's Hospital, "recent test results show that the minor improvements were only temporary," Griffin said.

"Based on medical advice, our focus is now on making Emily as comfortable as possible through in-home care, which will require around the clock care for an unknown amount of time, possibly months."

Emily slipped away surrounded by her loved ones.

Emily's final weeks were spent showering her friends and family with love, her obituary reads, "lighting up whenever her life partner and 'her rock', Will, was nearby, making her family laugh with jokes and eyerolls, planning celebrations for her friends, and bragging about her new nephew to her many visitors," it reads.

Emily graduated Fair Lawn High School and William Paterson University, before beginning her career as a preschool teacher. She was a cherished member of the BJ Wilkerson Memorial Child Development Center and DA Quarles Early Childhood Center.

Services will be held at theVander Plaat Colonial Home. Click here for funeral details and here to donate to the GoFundMe page for Emily.

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Paterson Teacher Dies After Battling Brain Infection, Cancer - Daily Voice

Berlusconi says he believes he’ll recover ‘once again’ – The Associated Press

ROME (AP) Former Italian Premier Silvio Berlusconi said he believes he will overcome the lung infection caused by a chronic leukemia that has hospitalized him in intensive care, Italian daily Il Giornale reported on Friday.

Its hard, but Ill make it once again, the 86-year-old media mogul said in a phone call with Il Giornales editor in chief, Augusto Minzolini.

I managed, also in delicate and difficult situations, to pull myself up, Berlusconi added, according to the report.

The media tycoon and three-time premier spent a second consecutive night in intensive care at Milans San Raffaele Hospital, where his doctors on Thursday signed off on a medical bulletin saying that he has had leukemia for some time, but that the cancer of the blood cells is in a persistent chronic phase.

The statement was the first official word from doctors since Berlusconi was admitted to San Raffaele on Wednesday.

The current treatment strategy envisions treatment of the pulmonary infection as well as specialized treatment aimed at limiting the negative effects of the chronic leukemia, the bulletin stated.

On Friday morning, Foreign Minister Antonio Tajani, quoting Berlusconis personal doctor Alberto Zangrillo, reported that Berlusconi was alert and was responding to the treatments. Tajani is the coordinator of Forza Italia, the political party that Berlusconi created some 30 years ago.

Berlusconi was admitted to an intensive care unit at San Raffaele Hospital on Wednesday for treatment of what aides indicated was a respiratory problem stemming from a previous infection.

The former premier and now senator had left the same hospital a week earlier after several days of tests.

Doctors said the kind of leukemia afflicting Berlusconi usually appears in people of advanced age and is characterized by an increase in white blood cells known as monocytes.

Treatment for older patients can involve a stem cell transplant. But that could be difficult, according to an Italian nonprofit association dedicated to combating leukemia. Another treatment would involve controlling the white blood cell count.

The last years have seen Berlusconi suffer numerous health problems, including heart ailments and COVID-19 in 2020, which saw him hospitalized then in critical condition with pneumonia.

He has had a pacemaker for years, underwent heart surgery to replace an aortic valve in 2016 and overcame prostate cancer decades ago.

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Berlusconi says he believes he'll recover 'once again' - The Associated Press

ChristianaCare Researchers Show That Cancer Stem Cell … – ChristianaCare News

April 4, 2023 Bruce Boman, M.D., Ph.D.

Researchers at ChristianaCares Cawley Center for Translational Cancer Research at the Helen F. Graham Cancer Center & Research Institute have demonstrated for the first time that microRNA (miRNA) expression leads to a diversity of cancer stem cells within a colorectal cancer tumor.

This diversity of cancer cells may explain why advanced colorectal cancer is difficult to treat. Study results have been released in the Journal of Stem Cell Research and Therapy.

The findings broaden the understanding of how miRNA expression adds to cancer stem cell diversity and may lead to more precise anti-cancer treatments for patients with advanced colorectal cancer. The research builds on prior discoveries by scientists at the Graham Cancer Center about how cancer stem cell activity contributes to the development and spread of colorectal cancer.

Our research shows at least in the laboratory that there are different subpopulations of cancer stem cells in a tumor, and they may be driving the growth of the cancer, said Bruce Boman, M.D., Ph.D., MSPH, FACP, principal investigator and medical director of Cancer Genetics and Stem Cell Biology at the Graham Cancer Center.

In one subpopulation of cancer stem cells, its miRNA will shut down the stem cell genes that are expressed in another subpopulation, and vice versa, within the same tumor.

The study focused on the composition of cancer stem cells within a colorectal cancer cell line (HT29) in the laboratory setting.

Researchers evaluated the different cancer stem cell subpopulations that were identified by examining patterns of miRNA expression in each subpopulation and looking for differences.

The researchers found that each of the four diverse subpopulations that were studied (ALDH, LRIG1, CD166 and LGR5) had a different miRNA expression or gene signature.

The researchers found that miRNA expression could inhibit the expression of messenger RNA (mRNA), which carries instructions from the DNA to encode specific proteins within cells. Therefore, miRNA, by controlling gene expression, dictate which proteins are contained in the stem cells. The researchers discovered the miRNA that are upregulated in certain cancer stem cell subpopulations are downregulated in other cancer stem cell subpopulations. In this way, differential miRNA expression leads to cancer stem cell heterogeneity within colorectal tumor tissue.

Its an early research finding and needs to be followed up with other experiments, but it has clear relevance to the clinic, Boman said.

The question is: Can you target the miRNA to make cancer more sensitive to certain treatments? Because we know what the current anti-cancer treatments are targeting, we may be able to modulate or manipulate the cancer, so it becomes more sensitive to the treatment.

For more than a decade, ChristianaCares researchers have contributed to the understanding of the role that cancer stem cells and miRNA expression play in the development and spread of colorectal cancer. This latest finding builds on earlier discoveries that examined a link between two cellular signaling pathways: retinoic acid (RA) signaling and wingless-related integration site (WNT) signaling, which are dysregulated by different gene mutations in colorectal tumors.

The RA signaling pathway induces growth arrest and differentiation of cancer stem cells. Notably, retinoic acid is effective against other types of cancer such as leukemia. The role of the WNT signaling pathway has an opposite effect on tumor growth. The WNT signaling pathway is activated by a mutation in the APC (adenomatous polyposis coli) gene in about 90% of cases of colorectal cancer.

In APC mutant tissue, dysregulated miRNA expression may underlie an imbalance between the RA and WNT signaling, which then leads to intratumoral cancer stem cell heterogeneity. Still, this mechanism that may enable the cancer to proliferate could also provide clues on how to more effectively treat cancer.

If youve got an imbalance between these two signaling pathways, then youve likely got a growth driver, Boman said. The question is: Can you suppress the WNT signaling and enhance the retinoic acid signaling?

It may be possible to increase the sensitivity of colorectal cancer to retinoic acid-type drugs, and therapeutically shift the balance between different cancer stem cell subpopulations, thereby suppressing cancer growth. More research is needed to determine how targeted cancer therapies containing retinoic acid-type drugs may be made more effective against advanced cancer.

This research will be presented at the annual meeting of the American Association for Cancer Research in Orlando, Florida, April 14-19.

This research project was supported by a grant from the Lisa Dean Moseley Foundation.

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Lymphoma caregiver: MD Anderson is not just my workplace it’s … – MD Anderson Cancer Center

My husband, Donald, and I had been dating for less than a year in June 2010, when he was diagnosed with B-cell lymphoma, a type of non-Hodgkin lymphoma.

We came to MD Anderson the following year because we hadnt seen any improvement in his condition, even after several months of lymphoma treatment with a local provider.

Thanks to MD Anderson, my husband was in remission by early 2012 and I was on a mission to become an occupational therapist here. Thats why I tell people today that MD Anderson didnt just save my husbands life. It also helped me to find my lifes work.

My husbands lymphoma symptoms

Donald first started showing symptoms of lymphoma in May 2010. It began with a pain on the left side of his abdomen. Shortly after that, he began having night sweats and developed a low-grade fever.

I was really worried about him. Don had always been super healthy and physically active. And while he did have a demanding, high-stress job, he was starting to feel much more fatigued than usual.

My husbands lymphoma treatment

At MD Anderson, we met with lymphoma specialist Dr. Fredrick Hagemeister. He said Donalds cancer was aggressive, but he was confident that we could treat it. He recommended several rounds of chemotherapy.

Donald began intensive chemotherapy to break up the tumor attached to his intestine. Then, Dr. Hagemeister suggested a stem cell transplant to keep the cancer in remission.

The stem cell transplant ended up being the last lymphoma treatment Donald needed, although a few months later, surgical oncologist Dr. Jean-Nicolas Vauthey had to remove portions of his small and large intestines because the cancer had damaged them.

My husband was formally declared in remission as of early 2012. He has shown no evidence of lymphoma since then.

Why it means so much to work for MD Anderson now

I was so grateful to MD Anderson for the care and consideration Donald and I received that I resolved to become an occupational therapist here. I achieved both of those goals in 2019, when I earned my certification as an occupational therapist and joined MD Anderson as an employee.

Now, Im a member of the same workforce that once saved my husbands life. This is incredibly meaningful to me. MD Anderson gave us our lives back, and I want to share that same gift with others.

As a caregiver and an employee at MD Anderson, I have always found the culture here to be warm, open and welcoming.

What I tell people about MD Anderson today

Today, Donald and I live on Galveston Island. So, it takes me about an hour and half to get to and from my job in the Texas Medical Center. But I feel like being a part of MD Anderson is worth sitting in traffic for.

Material things dont matter to me. You cant take them with you when you die. And the most important things in life like love, kindness, health and acceptance are things you cant buy.

MD Anderson gave us all of those things. So, its not just a workplace for me now. Its my passion.

Request an appointment at MD Anderson online or by calling 1-877-632-6789.

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Lymphoma caregiver: MD Anderson is not just my workplace it's ... - MD Anderson Cancer Center

Myelofibrosis: Indications for Treatment and Transplant – Targeted Oncology

Case: A68-Year-OldWomanwithMyelofibrosis

Transcript:

Abdulraheem Yacoub, MD: Different patients with myelofibrosis will have different triggers and different indications for therapy. Even patients with lower-risk disease might have therapeutic needs, such as managing anemia or proliferation, symptoms, and quality of life. However, patients with relatively high-risk disease have more immediate need for therapy. Through multiple clinical trials that were completed on myelofibrosis, we have identified that therapy with JAK-STAT inhibitors or JAK inhibitors has profound benefit to patients. They improve symptoms, reduce spleen size, and prolong overall survival. Weve also identified that a delay of therapy could be detrimental to patients who might lose months or years of their potential life expectancy, and they can progress to where they arent eligible for additional therapy. As soon as we identify patients with high-risk disease, we discuss immediate interventions. This has been proven to be of value, including additional survival advantage. With patients who continue to have lower-risk disease, we reevaluate them frequently for indications for therapy or any signs and symptoms of progression in which therapy should be applied immediately.

The only curative therapy for patients with myelofibrosis remains allogeneic stem cell transplantation. In this therapy, patients receive myeloid ablation with chemotherapy and then replacement of their bone marrow by allogeneic graft, which could be from a family member or an unrelated donor. The success of allogeneic stem cell transplantation in myelofibrosis has improved substantially over the last few years, especially with the application of JAK inhibitor therapy as a bridge to transplant, as therapy after transplant, and the improvement in supportive care measures.

Allogeneic stem cell transplantation has risks and complications, and its geared toward patients with relatively good general health, good performance status, and few medical comorbidities. We absolutely evaluate every patient under age 70 for up-front allogeneic stem cell transplantation. In some institutions, including ours, we evaluate patients up to age 75 for allogeneic stem cell transplant with curative intent. For patients who are over age 75, we select them very carefully for the benefit and risk of such intervention. In general, patients should be in fair health, with few or well-controlled medical comorbidities, and with adequate social and economic support and access to a center with expertise in transplantation.

We routinely offer initial evaluation for the majority of our patients who are in that age limit, for the availability of a donor and the lack of other contraindications. Many patients are found to be eligible. This should be evaluated early in the patients course. That way, we can plan their bridging therapies strategically so they get transplanted at their best health state. What does that mean? Weve confirmed repeatedly that a therapy with a JAK inhibitor has meaningful value to patients health. They have improvement in their well-being, spleen size, functional ability, and quality of life. A successful therapy with a JAK inhibitor can make patients even more fit for bone marrow transplantation. The incorporation of initial therapy, along with coordination with a bone marrow transplant, is the standard of care in these patients.

Routinely, we offer patients first-line therapy with a JAK inhibitor; we optimize that. We allow patients to achieve maximum response and then proceed with transplant in a controlled and planned setting, so patients have many months to prepare emotionally, physically, and medically with bridging therapy. This allows time to select the best donor, to optimize their life events, and for work- and family-related issues so the transplant can be at the ideal time for the patient. Often, its 3 months to 1 to 2 years based on their risk and based on how well they do with bridging therapy. There are also personal choices for patients and the ability for donors at the center.

Transcript edited for clarity.

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Myelofibrosis: Indications for Treatment and Transplant - Targeted Oncology

California man in HIV remission opens up about his rare medical … – The Washington Post

Paul Edmonds, 67, is one of a handful of people who are in remission from HIV following an experimental stem cell transplant. (Lauren Justice for The Washington Post)

April 3, 2023 at 6:00 a.m. EDT

Comment

DESERT HOT SPRINGS, Calif. In September 1988, an intern at San Francisco General Hospital told Paul Edmonds that he had HIV. Worse, the virus had already ravaged his immune system and progressed to full-blown AIDS. Edmonds was 33 that day. Having seen friends with HIV waste away in months, he assumed he would be dead within a year or two. Maybe sooner.

I remember how I felt inside when I heard, he said. I felt my heart sink.

Unlike most of his infected friends, Edmonds lived to see his 40th birthday, then his 50th, and his 60th. Then something extraordinary happened. In 2019, he became one of just five people in the world to receive a successful stem cell transplant from a donor with a rare genetic mutation that makes the body resistant to HIV.

In 2021, Edmonds stopped taking the medications he had depended on for half his life. Now 67 and living here in California, he is in long-term remission from HIV and leukemia.

Because of the risks involved in stem cell transplants, the treatment that effectively cured Edmonds is likely to remain extremely rare, reserved for patients with both HIV and cancer, said Ahmed Aribi, one of the doctors who treated him at the City of Hope cancer center in Duarte, Calif. As it stands, many HIV patients take antiretroviral drugs that have transformed the infection into a long-term, manageable condition.

But the knowledge scientists are gleaning from the handful of patients who have undergone stem cell transplants could unlock secrets about the virus that will lead to new treatments or vaccines.

Thats a long way from where we started, said Joseph Alvarnas, a professor of hematology at City of Hope.

Alvarnas began treating patients with HIV in 1985, as a medical student working at San Francisco General Hospital. Back then, patients newly diagnosed with AIDS-related lymphoma, a cancer of the immune system marked by weight loss, fever and drenching night sweats, had a median life span of just 30 days.

Today, Alvarnas said, there are thousands of Americans who, like Edmonds, have lived with HIV for many years, decades even. While the specifics of Edmondss story are unique, its broad strokes are emblematic of the long path America has followed in its fight against HIV, a journey from near despair to hope.

Where do we go from here?

Census figures show that more than 170 million Americans are probably too young to remember the early days of the HIV/AIDS crisis, but it was a time with intriguing parallels to the covid era. A new disease was spreading rapidly, killing in alarming numbers. Doctors and scientists scrambled to learn where it came from and how it might be stopped or slowed. Fear and misinformation spread, stigmatizing the infected and spurring conspiracy theories.

Its a time Edmonds and his husband, Arnie House, another longtime HIV survivor, remember all too well.

Raised Baptist, Edmonds grew up in the small town of Toccoa, Ga., about 100 miles northeast of Atlanta. At the age of 10, when he still had only a vague idea that he might be different from classmates, Edmonds said he learned a gay man had been beaten to death in Toccoa. Some residents said the man had deserved it.

Not until 1976, at age 21, would Edmonds tell family and friends what hed struggled to tell himself: He was gay.

Ill always love you, his father said. Just be the best person you can be. Shocked at first, Edmondss mother quickly adjusted and provided love and backing.

That year, Edmonds moved from Atlanta, where he had been working as a word processor typing documents, to San Francisco, and the change was incredible, he said. Gay men were flocking to San Francisco. Edmonds made friends easily. He celebrated. I didnt feel alone anymore.

Then, in 1980, people he knew began to get sick and die. At first, no one knew why. People called it the gay cancer, a term he despised.

Edmonds would sit in his neighborhood bar, the Deluxe, reading the obituaries in the Bay Area Reporter, a San Francisco newspaper. Often, the first he knew that a friend had even been sick was when he read the obituary. He would sit there crying, sometimes alone, sometimes with others.

Edmonds visited friends in hospitals. He attended funerals and life celebrations for the dead.

He felt healthy when he finally went to get tested for HIV in 1988, though he suspected that, like most of his friends, he had the virus.

One of the first things Edmonds did after learning that he had AIDS was to call his mother with the news; he had no siblings. His mother wept and said she would pray for him.

After receiving the diagnosis, Edmonds said, I let myself freak out. I probably drank too much, though I did get that under control at some point. Marijuana took on a much longer-term role in his survival. The drug countered the nausea, giving him an appetite, which in turn allowed him to avoid severe weight loss.

He did not plan his funeral, except to specify what he did not want. He did not want a religious service because he felt abandoned by religion. Nor did he want an open-casket funeral because he had not liked the ones hed attended while growing up. He asked to be cremated.

There were moments when Edmonds allowed himself to imagine death. How could I not? Yet he focused his mind on survival and did his best to banish despair. When he visited sick and dying friends, he never thought, Thats going to be me.

I tend to not give up, he said. Ever.

Edmonds tried dozens of medications, some of them experimental. The physical misery of AIDS the nausea, diarrhea and intense fatigue came not from the disease, but from side effects of the medications he took. He meditated and endured.

He felt sadness but also great anger that we werent getting the help that we needed. President Ronald Reagans first public mention of the word AIDS did not come until September 1985, according to numerous sources.

On the night of Feb. 23, 1992, Edmonds went to a bar, the Midnight Sun, in the Castro District of San Francisco. From across the bar, he and Arnie House, who had served in the Air Force, saw each other.

He was very talkative, and I thought he was very attractive, Edmonds said. There was just a lot to like.

Ditto, House said. I was just in awe of him.

When they spoke that first night, Edmonds explained that he had HIV.

I accepted it as normal, House said. I was enamored of him. That made it a lot easier.

Soon after that first meeting, Edmonds convinced House to get tested for HIV. The couple went to the test together. By this time, HIV treatments were improving, and so was the outlook for patients. The first of the effective protease inhibitor treatments was only a few years from receiving Food and Drug Administration approval.

When House learned that his test showed he had HIV, he took the news well. I said immediately, Where do we go from here?

We take care of each other, Edmonds replied.

That was indeed how their lives with HIV played out. When one was sick, it always seemed the other was well enough to care for him. House, who had worked for more than a decade as a nurse, proved comfortable in that role.

The two men drew up wills together. They accompanied each other to doctor visits. When they arrived home from medical appointments, they started researching what theyd learned from the doctors.

They collaborated on healthy diets, exercise regimens and the pros and cons of different medications.

Edmonds, who had painted before they met, returned to his art and taught House. They spent hours working over canvases. Edmonds, who had lived through dark times, adored the brightest colors sky blues, hot pinks and lime greens.

Painting, he said, was my happy place.

As years passed, the men discovered that for them, HIV was not a death sentence, but a fact of life. Edmondss 40th birthday celebration was bigger and better than his 35th. For his 50th, he threw a large party, hiring a jazz band and inviting 100 people. In 2014, Edmonds and House, then 58 and 57, respectively, were legally married.

But in August 2018, on one of his routine HIV checkups, Edmondss doctor analyzed his blood sample and discovered a problem. Although Edmonds felt no symptoms other than fatigue, he was diagnosed with a blood disorder called myelodysplastic syndrome. The disorder results in some newly formed red blood cells failing to grow correctly or to enter the bloodstream.

Edmonds was referred to City of Hope in Duarte, where doctors learned that the syndrome had progressed to acute myeloid leukemia, a cancer of the blood and bone marrow. To treat the cancer, he required a blood stem cell transplant, a procedure that carries a 10 to 20 percent risk of death.

However, Edmondss leukemia had one benefit. He learned that when doctors searched for a compatible donor, they would have the chance to address both his leukemia and his HIV. They would hunt for a rare mutation, known as CCR5 Delta 32, which occurs in only 1 to 2 percent of the population. The mutation prevents HIV from invading cells and multiplying.

The transplant would have been too dangerous had Edmonds had HIV alone. But it was recommended for leukemia, giving Edmonds and his doctors a rare opportunity. The procedure had been tried before with other HIV patients; it had worked just four times, starting in 2007 with Timothy Ray Brown, a man known at first as the Berlin patient.

Doctors were able to find a donor who had the rare mutation and was a perfect match for Edmonds. The transplant was scheduled for Feb. 6, 2019. After six days of chemotherapy to wipe out his immune system so that it could not attack the donor cells, Edmonds was ready.

Okay, the dates finally here, he remembers thinking.

The transplant, which took 20 to 30 minutes, went well. He did better than average, said Aribi, one of his doctors at City of Hope.

Edmonds passed the critical 100-day mark after the transplant, the time when complications are most likely to develop. For an additional couple of months, he was required to stay within close range of the hospital. At that point, old friends from Boston, Atlanta, Austin and Reno, Nev., came to stay with him.

No one wanted me to be by myself, he said. The friends treated the time as a reunion, accompanying Edmonds to some of his old haunts, including his former loft in the Flower District of Los Angeles.

Edmonds delayed stopping his HIV medications during the first year of the coronavirus pandemic, finally making the break on March 6, 2021.

The future of the HIV fight

The stem cell treatment, while unavailable to most patients, exposes a chink in HIVs armor, one scientists may be able to exploit years down the road should gene editing be proved safe in humans.

As one of a handful of HIV survivors who have gone into long-term remission, Edmonds is of keen interest to researchers.

Jana K. Dickter, an associate clinical professor with City of Hopes division of infectious diseases, said she is tracking Edmonds for two studies. One focuses on searching for reservoirs, small sites in the body where HIV can hide from the immune system, dormant but not producing new virus. The other study is trying to determine whether the virus can reactivate now that Edmonds has stopped taking HIV medications. So far, the studies have found no HIV reservoirs or signs that the virus is rebounding.

In the meantime, Edmonds has been visiting people who are sick and elderly, running errands and providing companionship. He has just begun sharing his own story.

Im a grateful person, he said. Somehow, miraculously, I survived all of this.

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California man in HIV remission opens up about his rare medical ... - The Washington Post

Accumen Appoints Distinguished Hematologist-Oncologist, Patricia Ford, MD, to its Medical Advisory Board – Yahoo Finance

Scottsdale, AZ, April 04, 2023 (GLOBE NEWSWIRE) -- Board-certified hematology-oncologist, Patricia Ford, MD has been appointed to the Comprehensive Patient Blood Management (cPBM) Medical Advisory Board at Accumen. Dr. Ford will provide guidance to Accumens Clinical Transformation Services and solution teams as they implement Patient Blood Management programs in hospitals and health systems nationwide.

Dr. Fords innovative and patient-centered approach to stem cell transplantation without the use of blood transfusions sets her apart as a distinguished and nationally recognized oncologist. We are excited that she is coming onboard and supporting our cPBM programs, said Sherri Ozawa MSN, RN, Director of Clinical Operations and Delivery at Accumen.

Dr. Ford currently serves as Director for both the Peripheral Stem Cell Transplant Program and the Center for Bloodless Medicine and Surgery at the University of Pennsylvania Health System. She is also a Founding Member and Past President of the Society for the Advancement of Patient Blood Management (SABM). Additionally, she has authored numerous publications about Patient Blood Management.

Dr. Ford received her doctorate from the University of Miami, completed her residency at the Graduate Hospital, and fellowship at Fox Chase Cancer Center. She was recognized in Philadelphia magazines annual Top Docs issues for 2018 and 2019, by Americas Top Doctors for 2017, and Best Doctors in America from 2005-2018.

Patient Blood Management is near and dear to my heart, and I am ecstatic to support Accumens world-class cPBM program. I look forward to aligning with and adding to Accumens clinical expertise, stated Dr. Ford.

About Accumen Inc.Accumen enables hospitals, health systems, and independent labs to respond to current challenges and even thrive in todays unpredictable and ever-changing environment. With a focus on lab operations, clinical transformation, and 3D imaging post-processing, Accumen leverages technology-enabled consulting services to solve complex hospital and health system issues. Based in Scottsdale, AZ with offices in Louisville, KY and Blue Bell, PA, Accumen accelerates results for more than 1,000 U.S. hospitals and health systems by providing expert resources, extensive operational and clinical data, as well as analytic technology.

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AccumenHelping Healthcare Get Better, Faster.Find out more at ACCUMEN.com

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Accumen Appoints Distinguished Hematologist-Oncologist, Patricia Ford, MD, to its Medical Advisory Board - Yahoo Finance