In MDS, Transplant Ups Survival in Elderly and May Be Reimbursed

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant — 47.9% vs 26.6% for the “no donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, Massachusetts, told Medscape Medical News.

Coauthor Ryotaro Nakamura, MD, from the City of Hope, Duarte, California, told Medscape Medical News that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, Massachusetts, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he told Medscape Medical News.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins School of Medicine, Baltimore, Maryland, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Brodsky said, predicting that “this study will change the standard of care”

Henry Fung, MD, chair of the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center, Philadelphia, Pennsylvania, agreed. “We should congratulate all the investigators and our patients who participate in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.”

“I will recommend all patients with intermediate-2 or higher risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Fung told Medscape Medical News.

Immediate Impact on Clinical Practice

Dr Corey Cutler

Lead author Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payor position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course in order to maximize search time and provide patients all potential options for therapy.

Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Brunner said.

Reimbursement by CMS for Medicare Recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.

Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Nakamura said, noting that the data is being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” Corey told Medscape Medical News.

The other study, published earlier this year in JAMA Oncology (2020;6:486-493), showed that outcomes for patients older than ager 65 were shown to be similar to those between ages 55 and 65.

BMT CTN 1102 Study Details

Cutler noted that the study was designed to address the issue whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been  approved by Medicare.

The multicenter study enrolled patients who were between age 50 to 75 years and had newly diagnosed MDS of higher risk (IPSS intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one third had a high comorbidity score, Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Cutler noted.

Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS — there is much room to improve,” he said.

Role for Alternate Donors

Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Brunner said. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”   

“I think a significant consideration here as well is health equity. Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis,” Brunner told Medscape Medical News.

Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Fung has disclosed no relevant financial relationships. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceutics, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Brunner reports relationship with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

American Society of Hematology (ASH) 2020 Annual Meeting: Abstract 75. Presented December 5, 2020.

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SABCS 2020: What's Hot, Including a Major Chemotherapy Trial

The “hottest” presentation at the upcoming 2020 San Antonio Breast Cancer Symposium (SABCS) comes from RxPONDER (abstract GS3-00), a major randomized clinical trial assessing use of a recurrence score among women with lymph node-positive, early-stage breast cancer to determine who might safely forgo chemotherapy.

That’s the word from Virginia Kaklamani, MD, from the University of Texas Health Sciences Center San Antonio. Kaklamani, a professor of medicine in the Division of Hematology/Oncology, is co-director of the meeting that runs online December 8-11.

If the new trial sounds familiar, that’s because it’s a lot like the TAILORx trial, the results of which were first presented in 2018 and have changed practice in women with early-stage disease and no lymph node involvement.

“This is the lymph-node positive TAILORx. It’s extremely important,” Kaklamani told Medscape Medical News, adding that both trials involved women with HR-positive, HER2-negative disease.

If the RxPONDER trial, she explained, shows similar outcomes between women randomized to adjuvant endocrine therapy alone vs endocrine therapy plus chemotherapy, then clinicians “can potentially avoid giving chemotherapy to a large number of women who are currently receiving it.”

Because women with nodal involvement (one to three positive axillary nodes) are at a higher risk of recurrence, RxPONDER may provide needed insight on the management of these types of breast cancers, Kaklamani suggested.

Both trials have used the 21-tumor gene expression assay (Oncotype Dx) to determine recurrence-risk status.

Kaklamani also spotlighted the phase 3 CONTESSA trial (abstract GS4-01) in 600+ patients with locally advanced or metastatic breast cancer that is HR-positive and HER2-negative and has been previously treated with a taxane.

The trial features an experimental oral taxane, tesetaxel. The primary objective is to compare the efficacy of tesetaxel plus a reduced dose of capecitabine (Xeloda) vs the approved dose of capecitabine alone. Presented data will include progression-free survival (PFS) results, indicating about a 3-month PFS advantage with tesetaxel, which is taken once every 3 weeks.

“Oral drugs are convenient for patients and, despite limitations, they are, all in all, a revolution in cancer treatment,” noted Kaklamani, adding that they beneficially eliminate the need for time-consuming infusions and related clinic visits as well as drug ports. 

It will be interesting to see what Steven Vogl, MD, a private practitioner in the Bronx, New York City, has to say about CONTESSA and the rest of the SABCS.

He is usually a commentator from the meeting floor, whose self-introduction, “Vogl, New York,” is well-known to perennial meeting attendees, as reported in a Medscape Medical News profile piece some years ago.

This year the medical oncologist will also serve as the chair of the “View from the Trenches” session, which is devoted to summarizing the meeting’s most important findings for everyday practitioners.

A number of years ago, Vogl proposed the idea of this where-the-rubber-meets-the-road session to SABCS meeting planners, which they then adopted. This year, Kaklamani invited Vogl to run the session and he accepted.

Vogl is a “really smart guy who is always right on” with his comments and questions, and he will be the first-ever independent, community-based oncologist to chair a meeting session, said Kaklamani.

Other Hot Topics

Another hot topic featured at the meeting will be the use of CDK4/6 inhibitors in the adjuvant treatment of HR-positive and HER2-negative disease that has a high-risk of recurrence, Kaklamani said. New data from two trials, monarchE and PENELOPE-B, will be presented.

First, there will be an update from the monarchE trial (abstract GS1-01). The first results from this trial were reported in September at the ESMO Virtual Congress 2020 and featured abemaciclib (Verzenio). The positive outcome represented the first treatment improvement in this high-risk setting in more than 20 years, according to experts.

A similar trial, PENELOPE-B (abstract GS1-02), looks at palbociclib (Ibrance) in a somewhat different population — those patients with high relapse risk after neoadjuvant chemotherapy. “These are even higher risk ER+ patients [than those in monarchE], which is why they received chemotherapy before surgery,” commented Kaklamani.

In triple negative disease, there will be overall survival (OS) results from the phase 3 KEYNOTE-355 study (abstract GS3-01) of pembrolizumab (Keytruda) vs placebo (plus chemotherapy for all patients) as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. “It’s potentially a huge deal,” said Kaklamani about the OS data, if they are statistically significant.

A meta-analysis (abstract GS4-08) of data on circulating tumor cells (CTCs), which are shed from the primary tumor into the bloodstream, may point to their value as a tool to determine whether or not a breast cancer treatment is effective. “CTCs allow you to assess how a treatment is doing before you do scans, which typically occur 3 months or so later,” explained Kaklamani.

CTC results can be assessed in 3 to 4 weeks and allow clinicians to change treatments if CTC volume increases. However, a previous study of CTCs did not show a clinical benefit with the tool among patients treated mainly with chemotherapies. What’s different about the new study, which is from an international group of investigators, is in the treatments patients with metastatic breast cancer received. “This study is from a different era — with targeted therapies,” said Kaklamani.

In the new study, changes in CTC levels (with a reduction being a good result) between baseline (pretreatment) and follow-up were analyzed to determine whether they were associated with overall survival.

COVID Sessions

On the meeting’s first day, SABCS will feature a special session on COVID-19 and breast cancer. The meeting organizers sought to separate the wheat from the chaff in this subject, as much has already been written, published, or presented.

“We received a lot of abstracts on COVID that were studies that were poorly done. We tried to tease through them and select the well-researched ones,” acknowledged Kaklamani.

The organizers included two patient advocates who have had COVID-19, including during treatment for breast cancer, as participants in the meeting session. The session will also feature global perspectives, with presenters from Brazil, Italy, and the Netherlands. 

Plenary Lectures

The meeting’s two plenary lectures will focus, respectively, on the increasingly used clinical approach of neoadjuvant therapy in breast cancer, and research in the time of a pandemic.

Elizabeth Mittendorf, MD, PhD, a surgical oncologist and director of the Breast lmmuno-Oncology program and co-director of the Breast Cancer Clinical Research Program at the Dana-Farber/Brigham and Women’s Cancer Center, Boston, will present “Local Regional Management Following Neoadjuvant Therapy: Minding the Knowledge Gaps.”

Ned Sharpless, MD, director of the National Cancer Institute (NCI), will present “Advancing Cancer Research During Challenging Times.”

Kaklamani has disclosed consulting fees with Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and contracted research with Eisai.

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay, MedPageToday and has had bylines on, MSNBC, and Yahoo. Email: and on Twitter: @MulcahyNick

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