Kyle Doherty joined MJH Life Sciences in 2021 and is the lead editor for 

as well as news and conference updates for OncLive.com. Email: kdoherty@mjhlifesciences.com

Promising techniques in surgical oncology are on the horizon for the treatment of
lymphedema, an incurable adverse event that can often arise after certain types of breast cancer treatment, according to Susan B. Kesmodel, MD.

“Anything that we can do as surgeons to primarily reduce lymphedema would be helpful for patients,” said Kesmodel, associate professor, director of Breast Surgical Oncology, and coleader of Breast Site Disease G at the Sylvester Comprehensive Cancer Center at the University of Miami Health System in Florida. “For patients who do develop lymphedema, if we can offer them both surgical and nonsurgical interventions, we can have a significant impact not only on their quality of life but [we] also could potentially reduce health care costs because the management of lymphedema can be very costly.”

In the past, lymphedema has primarily been treated with debulking procedures that remove the excess fluid through liposuction. These types of procedures typically provide only temporary improvement and do not address the condition physiologically. However, in recent years more physiologically impactful methods and considerations have been developed to curb the incidence and severity of lymphedema in patients with breast cancer.

Patients who undergo axillary lymph node dissection are at an increased risk for developing lymphedema. Kesmodel said that reducing the extent and instance of axillary surgery, as long as it is oncologically safe, can have a major effect on lymphedema rates in patients with breast cancer.

“The extent of axillary surgery has a significant impact on the development of lymphedema,” Kesmodel explained. “It’s more common in those patients who undergo axillary lymph node dissection; most of the studies have demonstrated that the risk in that patient group is around 20%. With the addition of radiation therapy, this number can increase to as high as 30% to 35%.”

The use of axillary surgery has been reduced in recent years using procedures such as sentinel lymph node biopsy (SLNB). Results from an evaluation of 125 patients who underwent SNLB or axillary lymph node dissection for the staging of breast cancer showed that SLNB had a significant effect in preventing lymphedema. Specifically, lymphedema was observed in 2 of 77 patients (2.6%) who underwent SLNB compared with 13 of 48 patients (27%) who had an axillary lymph node dissection.

 Additionally, a systemic review of data from randomized controlled trials, which examined 5161 patients who had SLNB, small numbers of adverse events were reported following the procedure including lymphedema (range, 0%-11%), pain (11%-16%), sensory disorders (2%-22%), and motor disorders (0%-9%) at 6 months after surgery.

Axillary reverse mapping is another technique that may reduce the extent of lymphedema in patients who undergo axillary surgery. The minimally invasive technique uses dye injection to distinguish and conserve upper-limb lymphatics during axillary surgery. In a randomized, controlled trial of 48 patients who had axillary lymph node dissection, 24 patients in the study group were treated using axillary reverse mapping, and 24 patients in the control group underwent a conventional axillary lymph node dissection. At the 6-month follow-up, lymph node visualization was achieved in 20 patients (83.3%) in the study group. The incidence of lymphedema was 16.7% in the control group compared with 4.2% in the experimental group.

Kesmodel said another option for managing lymphedema is lymphaticovenular anastomosis, also known as lymphovenous bypass. During this surgical procedure, a recipient vein is identified cutaneously and aided by lymphangiography, an anastomosis is created using microsurgical techniques. Several approaches can be utilized to perform the anastomosis, all requiring a microscope with high-magnification optics (TABLE

). The procedure requires time, meticulous technique, and experience.

Techniques to Reduce Incidence of Lymphedema in Patients With Breast Cancer

In a prospective evaluation of 100 patients with extremity lymphedema secondary to cancer treatment who underwent lymphovenous bypass, investigators observed symptom improvement in 96% of patients. A reduction in limb volume was seen in 74% of patients, with an average volume reduction of 42% at 12 months.

Findings from another single-center prospective study of 100 patients with upper and lower extremity lymphedema showed that, after a mean follow-up of 25 months, decrease in upper and lower limb circumference was observed in 52.1% of patients with a mean decrease of 6%. Patients in this study also completed a quality-of-life assessment using the Lymphoedema Functioning, Disability, and Health Questionnaire (Lymph-ICF). Mean Lymph-ICF score significantly decreased from a preoperative 43.9 to 30.6 postoperative, representing a significant improvement in patient-reported quality of life.

Of note, lymphaticovenular anastomosis comes with its own set of challenges. The procedure requires microvascular expertise and access to the necessary equipment, Kesmodel explained. There is also a concern for bleeding-related complications, although these have rarely been observed. In addition, allergic reactions may occur due to the use of isosulfan blue (Lymphazurin).

“If a more simplified lymphatic anastomosis approach is found to be effective, that is something that could potentially be used by a surgeon in any practice who doesn’t have access to advanced surgical techniques,” Kesmodel said. “A procedure like that could be more widely accepted and implemented across the United States and in countries around the world.”

Vascularized lymph node transplant (VLNT) to improve physiologic lymph clearance is a relatively new technique that presents another option for patients with lymphedema. Lymph nodes are harvested from a donor site with their supporting artery and vein and are then transferred to the recipient site of the affected area. Transplant nodes can be harvested from the groin, axilla, supraclavicular, submental, thoracic, and omental flaps.

VLNT carries the risk of donor site morbidity. Surgeons also must consider the possibility of iatrogenic lymphedema and the location of the scar.

“Lymphedema has been a problem for a long time,” Kesmodel concluded. “It is less of a problem now because we’ve reduced axillary surgery, among other things, but I still believe it’s a significant quality-of-life issue for patients and we really need to do our best to minimize it.”

Chang EI, Skoracki RJ, Chang DW. Lymphovenous anastomosis bypass surgery. 

. 2018;32(1):22-27. doi:10.1055/s-0038-1636510

Golshan M, Matin WJ, Dowlatshahi K. Sentinel lymph node biopsy lowers the rate of lymphedema when compared with standard axillary lymph node dissection. 

Pilger TL, Francisco DF, Candido Dos Reis FJ. Effect of sentinel lymph node biopsy on upper limb function in women with early breast cancer: a systematic review of clinical trials. 

. Published online January 30, 2021. doi:10.1016/j.ejso.2021.01.024

Faisal M, Sayed MG, Antonious K, Bakr AA, Farag SH. Prevention of lymphedema via axillary reverse mapping for arm lymph-node preservation following breast cancer surgery: a randomized controlled trial. 

. 2019;13:35. doi:10.1186/s13037-019-0217-1

Chang DW, Sumai H, Skoracki R. A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. 

. 2013;132(5):1305-1314. doi:10.1097/PRS.0b013e3182a4d626

Qiu SS, Pruimboom T, Cornelissen AJM, et al. Outcomes following lymphaticovenous anastomosis (LVA) for 100 cases of lymphedema: results over 24-months follow-up. 

. 2020;184(1):173-183. doi:10.1007/s10549-020-05839-4 

Gould DJ, Mehrara BJ, Neligan P, Cheng MH, Patel KM. Lymph node transplantation for the treatment of lymphedema. 

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Articles

Promising techniques in surgical oncology are on the horizon for the treatment of lymphedema, an incurable adverse event that can often arise after certain types of breast cancer treatment.

Surgical Considerations Emerge for Lymphedema Management

Although it is still true that not every case of relapsed multiple myeloma (MM) warrants immediate therapy, there is building evidence that novel combination therapies could be effective in treating early relapsed MM, according to data presented by Ajai Chari, MD, at the 2021 International Congress on Hematologic Malignancies.

“We see diminishing returns in relapsed disease,” explained Chari, the director of clinical research for the multiple myeloma program at Mount Sinai’s Ichan School of Medicine in New York, New York. “We can use hazard ratios to help guide therapy and selecting the proper treatment backbone is essential.”

Overall, the literature shows that the experimental treatment arms performed better than their control doublets. Chari explained that treatment backbones must be selected with prior treatments, patient demographics, and disease burden all taken into consideration.

Novel treatments utilizing a lenalidomide backbone showed an improved progression free survival (PFS) compared to the lenalidomide plus dexamethasone (Rd) control arms in phase 3 clinical trials. In the TOURMALINE-MM1 trial (NCT01564537), PFS in the experimental proteasome inhibitor ixazomib (Ninlaro) plus Rd arm was 21.0 months versus 14.7 months with Rd (HR, 0.74; CI 95%, 0.59-0.94).

In ASPIRE (NCT01080391), PFS was 26.1 months in the carfilzomib (Kyprolis) plus Rd group (Kd) compared with 16.6 months for Rd alone (HR, 0.66; CI 95%, 0.55-0.78).

 Data from ELOQUENT-2 (NCT01239797) showed that PFS was 19.0 months with elotuzumab (Empliciti), an anti-CS1 humanized monoclonal antibody, plus Rd group versus 14.9 months in Rd (HR, 0.71; CI 95%, 0.59-0.86).

 Finally, in the POLLUX trial (NCT02076009), the experimental arm of daratumumab (Darzalex) plus Rd showed a PFS of 45.5 months compared with 17.5 months for Rd (HR, 0.44; CI 95%, 0.34-0.55).

Treatments using a proteasome inhibitor backbone also produced better PFS in the experimental arms of phase 3 clinical trials compared to the bortezomib plus dexamethasone (Vd) control arms. Data from the BOSTON trial (NCT03110562) found PFS in the selinexor (Xpovio) plus Vd arm to be 13.9 months, while it was 9.5 months in Vd (HR, 0.70; CI 95%, NA).

 Results from BELLINI (NCT02755597) showed a PFS of 23.2 months in the group receiving venetoclax(Venclaxta) plus Vd, as opposed to 11.4 months with Vd (HR, 0.63; CI 95%, 0.44-0.89).

“Based on the randomized studies, the CD-38 and Kd regimens seem quite compelling, with a PFS of over 20 months,” Chari said. “Given a choice, I’d probably use CD-38 and Kd [first], but while also recognizing that not every patient is appropriate for the carfilzomib backbone—particularly someone with uncontrolled blood pressure, a cardiac history, or the very old. Those patients might be better suited to do a CD-38 with pomalidomide and dexamethasone combination.”

However, Ajai warned that cross-trial comparisons can be fraught due to differing patient populations, disease burdens, and prior therapy exposures. As a result, the outcomes of identical control arms can significantly vary between trials. Patient access to certain treatments at relapse also remains an issue.

In general, novel therapies improved outcomes for those with high-risk disease, but did not outperform the same techniques used in standard-risk patients.

PFS in the experimental arms declined in patients with lenalidomide-refractory disease in all the phase 3 studies examining the use of proteasome inhibitor backbones. PFS in lenalidomide-refractory patients was 9.5 months (HR, 0.61; CI 95%, 0.49-0.77) in OPTIMISMM (NCT01734928), 7.8 months (HR, 0.31; CI 95%, 0.24-0.39) in CASTOR (NCT02136134), and 8.6 months (HR, 0.53; CI 95%, 0.44-0.65) in ENDEAVOR (NCT01568866).

 These PFS figures all exceeded their control counterparts, but all fell short of the same therapy in standard-risk patients.

Chari A. Managing early relapse in multiple myeloma. Poster presented at 25th Annual International Congress on Hematologic Malignancies; February 28, 2021. Accessed March 1, 2021. https://bit.ly/3uN3PMG

Monreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. 

 2016;374:1621-1634. doi:10.1056/nejmoa1516282

Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. 

2018;36(8):728-734. doi:10.1200/jco.2017.76.5032

Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. 

2018;124(20):4032-4043. doi:10.1002/cncr.31680

Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. 

2020;34(7):1875-1884. doi: 10.1038/s41375-020-0711-6

Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study. 

2020;38(suppl 15):8501. doi:10.1200/jco.2020.38.15_suppl.8501

Kumar SK, Harrison SJ, Cavo M, et al. Updated results from BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. 

2020;38(suppl 15):8509. doi:10.1200/jco.2020.38.15_suppl.8509

Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. 

 2019;20(6):781-794. doi:10.1016/s1470-2045(19)30152-4

Weisel KC, Sonneveld P, Mateos MV, et al. Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) versus bortezomib and dexamethasone (Vd) in first relapse patients (pts) with multiple myeloma (MM): four-year update of CASTOR. 

2019;134(suppl 1):3192. doi:10.1182/blood-2019-123527

Dimopoulos MA, Monreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. 

 2016;17(1):27-38. doi:10.1016/s1470-2045(15)00464-7

There is building evidence that novel combination therapies could be effective in treating early relapsed multiple myeloma. 

Novel Combination Therapies Show Promise in Managing Early Relapse in Multiple Myeloma 

AbbVie and Caribou Biosciences, Inc have announced that the companies have entered into a collaboration and license agreement for the research and development of chimeric antigen receptor (CAR) T-cell therapeutics.

The terms of the multi-year agreement will allow AbbVie to utilize Caribou’s next-generation Cas12a clusters of regularly interspaced short palindromic repeats (CRISPR) hybrid RNA-DNA (chRDNA) genome editing and cell therapy technologies to research and develop 2 new CAR T-cell therapies. AbbVie will be given exclusive rights to Cas12a for the targets of their choosing. Caribou will perform certain pre-clinical research, development, and manufacturing activities for the collaboration programs, while AbbVie will handle development, commercialization, and other manufacturing efforts.

A $40 million upfront cash payment and equity investment will be directed to Caribou, as well as up to $300 million in future development, regulatory, and launch milestones. Additionally, there will be the potential for Caribou to receive additional payments for commercial milestones and global tiered royalties. AbbVie has the option to expand the collaboration to include an additional 2 CAR T -cell therapies for a fee.1

“Caribou’s next-generation CRISPR genome editing technologies hold broad promise for new therapy development,” Rachel Haurwitz, PhD, president and CEO of Caribou said in an interview with 

®. “A partnership with AbbVie allows Caribou to increase the number of targets and diseases addressable by these technologies. It’s an important opportunity to expand upon what we hope to do for patients. The collaboration is also an important validation of Caribou’s differentiated next-generation CRISPR genome editing technologies.”

CRISPR gene editing technology utilizes modular, biological tools to induce DNA changes in living cells. The 2 basic components of CRISPR systems are the nuclease proteins and the RNA molecules. The nuclease proteins cut DNA while the RNA molecules guide the nuclease to generate a site-specific, double-stranded break, which result in editing at the targeted genomic site. CRISPR systems are differentiated by the presence of a class 1 multiprotein effector complex or a class 2 single effector protein.

CRISPR systems have been shown to achieve several different types of genetic modifications in different types of cells. CRISPR techniques have achieved recombination, engineered immunity, mutagenesis, and donor-mediated gene disruption in bacteria, yeast, and filamentous fungi cells. The technique has also been used to achieve RNA-guided gene editing in multiple human cell lines with high specify and efficiencies of up to approximately 50%.

CRISPR systems can sometimes unintentionally edit certain genomic sites, leading to harmful effects on cellular function. Caribou’s chRDNAs are highly specific RNA-DNA hybrid guides that are used in combination with CRISPR to direct more precise genome editing.

“Caribou utilizes CRISPR hybrid RNA-DNA guides that contain both DNA and RNA nucleotides,” Haurwitz explained. “These hybrid guides drive much more specific genome editing than all RNA guides. Caribou uses chRDNA guides in concert with a CRISPR enzyme to develop complex immune cell therapies.”

By using CRISPR technology to engineer CAR T-cells to withstand host immune attack, Caribou hopes to develop “off-the-shelf” cellular therapies aimed at benefitting a broad patient population. The company is currently focusing on genome-edited off-the-shelf allogenic CAR T-cell and natural killer cell therapies for the treatment of patients with intractable malignancies.

Current programs in the discovery phase include CB-011 and CB-012 which use T cells to target BCMA and CD371 for patients with hematologic malignancies, respectively. Another product, CB-020, focuses on using natural killer cells therapies for an undisclosed target for patients with solid tumors. The CB-010 program, currently in phase 1 exploration, uses T cells to target CD19 and for patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

“I am excited about the opportunity for our companies to collaboratively develop 2 additional CAR T- [cell products], expanding upon the total number of therapies Caribou’s technologies underpin,” Haurwitz concluded.

AbbVie and Caribou Biosciences announce collaboration and license agreement for CAR-T cell products. News release. February 10, 2021. Accessed February 21, 2021. 

https://www.prnewswire.com/news-releases/abbvie-and-caribou-biosciences-announce-collaboration-and-license-agreement-for-car-t-cell-products-301225509.html

Pioneering chRDNA guides. Caribou Biosciences. Accessed February 21, 2021. 

Donohue PD, Barrangou R, May AP. Advances in industrial biotechnology using CRISPR-cas systems. 

2018;36(2):134-136. doi:10.1016/j.tibtech.2017.07.007

Cameron P, Coons MM, Stenberg SH, et al. Harnessing type I CRISPR-Cas systems for genome engineering in human cells. 

2019;37:1471-1477. doi:10.1038/s41587-019-0310-0

Pipeline. Caribou Biosciences. Accessed February 21, 2020. 

February 23, 2021 - AbbVie and Caribou Biosciences, Inc have entered into a collaboration and license agreement for the research and development of chimeric antigen receptory T-cell therapeutics. 

Caribou and AbbVie Initiate Development Partnership for CAR T-Cell Products 

Dana-Farber Cancer Institute has announced the launch of its first-ever venture fund, Binney Street Capital, LLC.

Binney Street Capital will aid new research and technology development to further Dana-Farber’s mission of developing treatments for incurable cancers. The primary focus of the fund will be therapeutics, while also considering investments in novel diagnostics, digital health, and services companies. Investments will be directed toward startup companies that are either created with Dana-Farber intellectual property or are cofounded by a Dana-Farber investigator.

“It’s a fairly new, exciting effort,” said Luba Greenwood, Managing Partner of Binney Street Capital in an interview with 

. There are other types of investors in oncology, but they are not cancer institutes. There are investors that are just venture capital firms. For example, pharma companies have strategic venture arms where they’re investing in oncology. This is actually quite differentiated, really a new model for investment.”

“We can continue to find some really amazing therapies, help them grow, help our scientists start companies in really exciting areas, and then take the money and reinvest it back into the science and help the scientists again,” Greenwood added. “That’s really the ultimate goal, to provide the funding and support to the scientists at Dana-Farber.”

The fund will be helmed by an advisory group of leading investors and industry experts who are dedicated to advancing Dana-Farber’s mission. Plans for the first 3 years include investments in 8 to 10 companies ranging from $250,000 to $2 million.

“Our goal is really furthering the mission of Dana-Farber,” said Greenwood. “That’s both a short-term goal and a long-term goal. Dana-Farber has 2 parts in this mission: one is to find cures for cancer and the other is to provide the best treatment. For us, consistent with and furthering that mission, we’re looking to support, help start, and seed companies in the cancer and oncology space and in the endocrinology space that are truly finding cures.”

Dana-Farber has previously helped build several cancer-focused biotech companies leveraging research and intellectual property to aid over 50 startups, 11 of which have debuted in the past 3 years. In early 2020, Dana-Farber partnered with health care investment firm MPM Capital to raise $100 million to invest into early-stage biotech companies developing therapeutic cancer technologies. In addition, the 2 partners raised over $26 million through the Dana-Farber Innovations Research Fund, which aimed to support early-stage oncology research at the institute.

“It’s quite unprecedented to have an opportunity to work with the best of the best of both physicians and scientists in cancer. It’s a remarkable, amazing opportunity to work with these people and to drive the science forward,” Greenwood said. “Not just with a concentration in therapeutics, but diagnostics as well, and other areas where we could potentially achieve true innovation for cancer patients.”

Dana-Farber Cancer Institute launches investment fund to support startup companies. News release. Dana-Farber Cancer Institute. January 14, 2021. Accessed on January 21, 2021. 

https://www.dana-farber.org/newsroom/news-releases/2021/dana-farber-cancer-institute-launches-investment-fund-to-support-startup-companies/

Bell J. Dana-Farber launches venture fund targeting incurable cancers. 

. January 15, 2021. Accessed January 21, 2021. 

https://www.biopharmadive.com/news/dana-farber-venture-fund-biotechs-cancer/593483/

January 29, 2021 - Dana-Farber Cancer Institute has announced the launch of its first-ever venture fund, Binney Street Capital, LLC. 

Kyle Doherty

Articles

Surgical Considerations Emerge for Lymphedema Management

Novel Combination Therapies Show Promise in Managing Early Relapse in Multiple Myeloma

Caribou and AbbVie Initiate Development Partnership for CAR T-Cell Products

Dana-Farber Unveils Venture Fund to Aid in Mission to Develop Options for Incurable Cancers