Hypomethylating Agents Show Promise in Myelofibrosis Progression After alloHCT

Donor chimerism was restored with hypomethylating agent (HMA) treatment among some patients with myelofibrosis (MF) who relapsed after allogeneic hematopoietic cell transplantation (alloHCT), according to a small retrospective published in the journal Transplantation and Cellular Therapy.

These data suggest that HMA “is an option for patients in the future,” the researchers wrote in their report. “By promoting restoration of donor chimerism and clearance of pre-alloHCT somatic mutations, HMAs offer a capable therapeutic strategy for improving outcomes in this challenging patient population.”

In the single-center, retrospective study, the researchers analyzed data from the electronic health records of 12 patients with MF who relapsed after alloHCT between 2020 and 2023 and were subsequently treated with an HMA.

The median age of the cohort was 61 years and 33% of patients had primary MF, 41.7% had post-essential thrombocythemia MF, and 25.0% had post-polycythemia vera MF.

There were 92% of patients with disease classified as intermediate-2/high-risk by the Dynamic International Prognostic Scoring System (DIPSS) and 83% were considered high or very high risk by the Molecular International Prognostic Scoring System (MIPSS70+). There were 66.7%, 25.0%, and 16.7% of patients with JAK2MPL, or CALR driver mutations, respectively, at diagnosis.

After transplantation, 99.9% of patients achieved donor chimerism at day 30 and 96.6% at day 100. Patients relapsed after alloHCT within a median of 282.5 days (range, 96-2388 days). The median donor chimerism before initiating an HMA was 57.82%.

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Novel approach may eliminate survival disparity in HSCT, greatly expand access

September 17, 2024

Key takeaways:

  • Post-transplant cyclophosphamide prophylaxis reduced the OS disparity in matched vs. mismatched unrelated donor hematopoietic stem cell transplant.
  • The approach could expand access to HSCT.

Use of post-transplant cyclophosphamide prophylaxis to prevent graft-versus-host disease could greatly expand access to hematopoietic stem cell transplantation, according to results of a retrospective study.

An analysis of patients who received post-transplant cyclophosphamide (PTCy) showed no statistically significant difference in OS or GVHD-free RFS (GRFS) between patients with matched (8/8) or mismatched (7/8) unrelated donors.

The ability to find a suitable unrelated donor with a 7/8 HLA match is “much greater” than finding one with 8/8 HLA match, according to researcher Steven M. Devine, MD, chief medical officer at NMDP and senior scientific director at Center for International Blood and Marrow Transplant Research (CIBMTR), told Healio.

“For an African American patient, [chances] go from 30% to over 80%,” Devine said. “It’s even higher for Hispanic or Asian individuals — into the 90% range.

“If you can go even lower [to a 6/8 match or 5/8 match], you can pretty much find a volunteer unrelated donor for almost 100% of patients,” Devine added. “We are enabling a transplant for everyone, regardless of their ancestry.”

Access disparities

Allogeneic HSCT — used to treat multiple blood cancers and blood disorders — produces the best results when stem cells of a related or unrelated donor matches at 8/8 HLA markers at the HLA-A, -B, -C and -DRB1 genes, according to study background.

Only 30% of patients have siblings, who are HLA-identical matches and therefore could donate.

Non-Hispanic white individuals have a 79% likelihood of finding an unrelated matched donor in the NMDP registry. The rate is between 29% and 58% for people of other races and ethnicities.

“Historically, there’s been roughly a 10% lower chance of survival with each level of mismatch,” Devine said. “That’s why for years the focus has been on trying to find full matches for all patients.”

Cyclophosphamide, a chemotherapy drug used to treat a variety of solid tumors and hematologic cancers, has been repurposed for about 20 years to prevent GVHD after HSCT.

“It’s really revolutionized [stem cell transplant] because its use is associated with a much lower risk for both the acute and more chronic forms of GVHD,” Devine said. “It’s improved outcomes overall, and it’s allowed us to perform mismatched transplants both from related and unrelated donors. So, [for this study], we [wondered whether] those historical differences in outcomes between matched and mismatched transplant [are] as great as they were years ago now that we’re using PTCy.”

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Donor Type Impacts Survival in MF Cell Transplantation

Patients with myelofibrosis (MF) who receive hematopoietic cell transplantation (HCT) from a matched sibling donor appear to have better overall survival (OS) than those who receive transplants from other donor types, according to a recently published study in Blood Advances.

“Understanding the impact of donor type is crucial not only to improve the clinical outcomes with HCT but also to establish the donor pool with viable options and eventually improve access to HCT,” the authors wrote.

HCT is currently the only disease-modifying therapy available for MF, the study team noted. The outcome after transplantation is diverse and dependent on several disease- and patient-associated factors, they added. According to recent research, donor type could also influence the prognosis of patients with MF after HCT. One study showed that patients with matched sibling donors had a better OS than the rest.

However, previous research has not taken the impact of posttransplantation cyclophosphamide for graft versus host disease prophylaxis into consideration, the researchers noted. Furthermore, no patients in previous studies had received vHLA-haploidentical donor grafts, they continued.

Therefore, the authors aimed to assess the impact of donor type in OS, considering the factors above and using the Center for International Blood and Bone Marrow Transplant Research registry data for HCTs done between 2013 and 2019. The study included over 1000 patients who received HCTs for MF.

Results showed that similarly to previous findings, matched sibling transplants were associated with better overall survival and lower graft failure than the rest. However, OS was only superior to the rest in the first 90 days after transplant. There was no significant difference in OS among patients who received mismatched unrelated, matched unrelated, and haploidentical donor transplants.

Despite the findings, the authors remarked that HCTs should not be delayed in the search for fully matched donors and highlighted the need for solutions regarding graft failure.

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A Caregiver’s Story: The Journey of a Spouse Through the Transplant Process

In March, MPN Advocacy & Education International highlighted the story of a recent stem cell patient, Andrea (click here to view story). This month, Andrea’s wife, Denise, shares her story as a caregiver in an interview with us. 

Andrea and Denise

How did you feel about your spouse’s decision to have a transplant? Were you apprehensive? 

I have been a part of Andrea’s medical journey since her diagnosis from ET to myleofibrosis.  I recall it took me about a week to learn how to pronounce the name correctly, and it has been an education ever since.  Being present during doctor appointments and multiple clinical trials provided first-hand information in addition to our ongoing discussions.  Observing and experiencing her five years of transfusion independence was a gift.  We took advantage of the opportunity to cycle and travel together and separately. Knowing the clinical trial would either end or the drug would quit working was only a matter of time.  And knowing how she physically felt prior to and after this time period played a role in my ‘wrapping my head’ around a possible future transplant.  All the while, we adjusted and modified activities as needed in order to continue allowing her to live life to the fullest.

When medications were no longer yielding the same results, and Andrea’s blood transfusions became more frequent, the doctors felt the alternatives were to continue clinical trials and hope for the best or discuss a stem cell or bone marrow transplant. I felt she was strong enough physically to beat the odds. It was now or never. I never doubted our decision, and have had no regrets.

How did you prepare yourself as a caregiver? 

In order to prepare, I scoured MD Anderson’s educational resources to understand what a ‘typical’ transplant journey would entail.  I developed multiple spreadsheets to track medications, nutrition, recovery, therapy, etc. I left the online myleofibrosis forum readings to Andrea as she would report her findings from reading first-hand accounts.  She also talked to many individuals who had had transplants, pummeling them with questions.

Another important piece of this journey was my mindset.  I focused on the end goal – her successful transplant and healthy recovery.  I looked at the journey in three parts:

  1. Pre-transplant
  2. Transplant/hospital stay
  3. Post-transplant

My goal was to have as much of her daily care and needs become second nature to me prior to her hospital release. When she was released, the additional environmental interaction was familiar without the distraction of ‘everything new all at one time’.

What tools did you find useful as the caregiver and advocate?

I created a 3-ring notebook with tabs to manage spreadsheets, medical records/test,  and doctor questions, so I could access information easily and quickly. I created a spreadsheet to track her medication schedule.  The purpose was to help me identify what was needed, including dosage when refilling medications both inside and outside the hospital. Click here to view medication tracker template. (For an Excel spreadsheet version of the attached please email kmichael@mpnadvocacy.com).

I also knew there was a good possibility that after her hospital release and within the first 100 days, she would have a trip to the emergency room and be re-admitted to the hospital.  Therefore, medications and ‘the notebook’ were kept in one location and easily picked up and transported with us.  The notebook was with us each time we visited the care team.

I created additional spreadsheets to help track:

  • Food and water daily intake and output. This is useful for doctor & nutrition appointments.
  • Daily stats: blood pressure, temperature, pain levels, exercise, spirometer therapy.  This is useful for tracking blood pressure and temperature anomalies.  Because if her temperature rose to a specific number, she had to go to the emergency room immediately.
  • Signs of graft vs host disease (GVHD).
  • I choose to stay in the hospital 24/7 to understand how the nursing staff/care team handled her care. This experience helped me understand her routine.
  • I figured if I learned her hospital routine, it would be familiar when she was released.
  • I used my smartphone and set alarms with labels so I knew what drugs were due when. (Used upon hospital release.)
  • I utilized Caring Bridge (www.caringbridge.org) to communicate Andrea’s transplant journey to her friends and family. My intent with each post was to create an engaging story yet convey “a day in her life” so everyone could get a sense of being there.

What was the most challenging part of your role and why?

Coming home and changing environments automatically kicked us back to normal behaviors and patterns. I felt we had to be more careful and diligent in preventing infection.  Even though we were home, I had to be more watchful because familiarity brings about a relaxed state.  Her immune system was developing and the risk of infection was too great.  Andrea quickly tired of me saying “No, you can’t do that or touch that.”

Once home, Andrea’s friends visited.  This was a considerable risk to her because the natural tendency is to hug and touch. To reduce her risk, we asked people to use hand sanitizer when they were around her.  We developed a routine where I would greet her friends first with a hug and explain she couldn’t hug yet. Andrea stood back a few feet to reduce her availability.

What I learned :

Every recovery and journey is different.

While it’s tempting, don’t measure your progress against someone else.  It’s your journey.  That goes for both the patient and caregiver!

The “notebook” was a great tool.  It kept us on schedule for all medications and were able to provide information to the doctors as needed.

The hospital care team staff is a critical part of your recovery.  Don’t opt for staying close to home if you feel a facility’s care team is better in another location.

Deciding where to have the transplant included researching the number of myleofibrosis transplants, versus other blood disease transplants, and the success that facility had.

Participate in the journey. I chose to shave my head at the same time Andrea did.  It sure made showering quick and easy!

Take in the outdoors and/or change the scenery.

Exercise or go for walks.  Listen to music.  Visit a friend. Go to the grocery store.  Do something to clear your head and regain perspective.

Have a confidante. It’s normal to question, or become frustrated, and to second guess.  But remember – it’s temporary.

You are the coach, cheerleader, and guardian all at once.  Embrace the many hats you will wear!

Click here to read Andrea’s Transplant Story 

MPN Patient Daily Stats 06-10-18