Unique Stem Cell Transplants for Grandfather and Grandson

MDS UK Chairman, Ted Peel, and his grandson, Romain, are set to receive stem cell transplants within weeks of each other.

Their generosity in sharing their moving story is doing wonders to raise awareness on MDS, encourage people to become stem cell donors and generate essential financial support for MDS UK and Teenage Cancer Trust.

On 20/08/2020 our article was published on the Metro, the highest-circulation print newspaper in the UK!
Click here to read the Metro story

Ex-lawyer Ted was diagnosed with MDS in 2015 following extreme fatigue, regular coughing up and passing of blood and several bone marrow biopsies.

“Following an unsuccessful period of G_CSF to remedy low a white blood cell count, I was hospitalised three times with sepsis where my temperature plummeted to 32C”, says Ted.

“Fortunately, I found considerable support and knowledge within the MDS Patient Support Group, a charity supporting patients and carers.”

MDS (Myelodysplastic Syndromes) is a group of malignant blood disorders in which the bone marrow fails to produce healthy blood cells. All types of blood cells can be affected, causing a range of symptoms, anaemia and frequent infections being amongst the most common ones. Ted was prescribed prophylaxis antibiotics to prevent further infections, but they continued including some in his mouth, triggering hospital admissions and weight loss.

“My transplant treatment scheduled for this spring was sadly postponed as it was deemed too unsafe for me to be admitted to the hospital due to Covid19”, says Ted.

Fortunately, he was told in July that he would be admitted promptly for the treatment at Kings College Hospital as cases of Covid19 in London have decreased.

“It’s great to be given another chance at life”, says Ted. “I want to say thank to MDS UK and the doctors and nurses in the Haematology Dept. of the hospital for their support."

Romain began experiencing migraine headaches and fatigue while studying for A Levels and was prescribed pain medication in the belief that exam stress was the cause.

After a prolonged period of deterioration and persistence by his Mother and Grandmother, he was finally diagnosed with Acute Lymphoblastic Leukaemia (ALL) in September 2019.

“However, more support is necessary, and we want our combined journeys help to generate essential funds for our respective favourite charities- MDS UK Patient Support Group and Teenage Cancer Trust”, says Ted.

MDS UK provides an array of support for MDS patients and recently funded its first research project, aiming at repairing damaged DNA in blood cancer. This would have positive implications for all blood cancers.

“Teenage Cancer Trust’s special hospital wards, nurses and youth support teams provide patients with emotional and practical support to get them and their families through some unimaginably hard times”, says Helen Farquharson, Senior Fundraising Manage at TCT.

“Romain is currently on a Teenage Cancer Trust ward” says Christine Peel, Romain’s Grandmother. “As well as supporting Romain, the charity’s staff there have been helpful, giving his Mum information, advice and directing her to support services. Their support has been invaluable.”

Both organisations need more financial support to ensure other patients have an easier time, especially during Covid19, which has seen the demand for services increase.

“We also urge more people to become stem cell donors, especially those from ethnic minority communities”, says Ted. “We would like to see a future where every blood cancer patient has a donor available and where cost is not an inhibiting factor."

“I believe every life matters and I’m tired of seeing people pass away too soon. I want to give something back as Christine and Ted are good friends of mine.

I just want to do something. I want people to realise that everyone has their own struggles and to make the most of what you’ve got because it can change so quickly.

I always try to keep smiling, help people along the way and treat others as I want to be treated.

If I can save even a few people, then that would mean something to me.”

On the 22nd of July, we had a very informative nationwide meeting on Clinical Trials and Research in MDS & AML During CoVid. Our Guest Speaker was Dr Austin Kulasekararaj, Consultant Haematologist at King's College Hospital.

Forty people attended the meeting, and Dr Kulasekararaj gave an introduction to the subject, tailored to the audience, and addressed patient's questions.

As you may already know, The Great North Run – one of MDS UK’s biggest annual fundraisers was sadly postponed due to the Covid19 pandemic.

Fortunately, the organisers have devised an excellent way to keep you running and raising essential funds for our life-changing work: The Great Run Solo, a virtual running challenge to keep you moving and raise funds for the NHS. There are weekly and monthly challenge options, as well as challenges for kids. Select the challenge that best fits your fitness & aims and get running. It just has to be done within the allotted 7 or 28 days.

The "Great North Run Solo" launched on 28th June (the birthday of the Great North Run) and “runs” until 13th September - the day the 40th GNR was scheduled.

To complete the challenge and claim a special edition Great North Run Solo medal, runners need to complete 40 runs (minimum) of any distance over the next 78 days.

It costs just £10 to join, and while all entry profits will go to the NHS Charities Together Covid19 Urgent Appeal, you can allocate your raised funds to MDS UK!

We need as many of our wonderful runners, new and old, to take part in this event so we can continue to support MDS patients and their loved ones through Covid and beyond.

The challenge is also an excellent opportunity to soak up some summer rays and with no distance target, you can go at your own pace!

For more information and to enter the challenge, click here.

For any fundraising related queries, please get in touch with us on fundraising@mdspatientsupport.org.uk

For many years, chronic myelomonocytic leukemia (CMML) has been treated as a form of myelodysplastic syndrome (MDS), despite its unique clinical and biological characteristics.

“Everyone recognized that, clearly, there were some patients who had highly proliferative features that weren’t at all typical of MDS, but CMML was still considered to be part of MDS for decades,” Mrinal Patnaik, MBBS, a hematologist at the Mayo Clinic in Rochester, Minnesota, told ASH Clinical News.

Inclusion of CMML under the umbrella of MDS for so long – beginning with the 1976 and 1982 French-American-British MDS classifications – has hindered a deeper understanding of the disease that might have resulted from studying it as a separate entity. There also are no CMML-specific approved drugs.

In recent years, clinicians and researchers have ramped up efforts to clarify the pathogenesis, natural disease progression, and presentation of CMML. ASH Clinical News spoke with Dr. Patnaik and other specialists about these efforts, as well as the challenges of defining uniform response criteria to guide clinical trials of CMML-specific treatments.

What Is CMML?

CMML is a clonal hematopoietic stem cell disorder that frequently progresses to acute myeloid leukemia (AML). It is classified as a rare disease and is estimated to occur in four of every million people in the U.S. each year. It occurs more commonly in men and rarely in young people – 90 percent of the people diagnosed with CMML are age 60 or older.⁽¹⁾

Its incidence may be slightly higher than previously estimated, according to Eric Padron, MD, from the Moffitt Cancer Center in Tampa, Florida, because it often is recognized only when a patient with MDS seeks a second opinion. The disease is an “overlap” syndrome that displays characteristics of both MDS (such as peripheral blood cytopenias) and myeloproliferative neoplasms (MPNs; such as leukocytosis and splenomegaly).

The 2001 World Health Organization (WHO) classification of leukemias and other hematopoietic neoplasms first separated CMML from MDS and created a distinct category of MDS/MPN overlap syndromes. In 2008, the WHO separated CMML via blast proportion into CMML-0 (<5% blasts), CMML-1 (5-9% blasts), and CMML-2 (10-19% blasts). Finally, in 2016, the WHO again revised its classification, including recommending that CMML be classified into two subtypes: proliferative (MPN-CMML) and dysplastic (MDS-CMML) depending on the patient’s white blood cell count.⁽²⁾

Dr. Patnaik said that the WHO’s decision to confirm that CMML should not be put into either MDS or MPN but should stand alone was a positive step forward. In addition, investigators have identified certain genetic mutations such as SRSF2, ASXL1, CBL, SETBP1, and JAK2 that are not exclusive to CMML but are more commonly found in patients with CMML than MDS without proliferative features, which can aid diagnosis.

Expected survival for patients diagnosed with CMML ranges from just a few months to a few years, depending on a variety of risk factors that are not yet well defined.

Fifteen to thirty percent of patients will progress to AML, at which point survival rates drop to 4.7 months without a hematopoietic cell transplantation (HCT) and 14.3 months with an HCT.

“The whole story with CMML is that it is a spectrum in the process of evolution to AML,” said Dr. Patnaik. “So, about 30 percent of all patients with CMML will eventually transform to AML within three to five years. When that happens, survival is very poor.”

One known prognostic factor for survival is CMML subtype. The dysplastic and proliferative subtypes affect patients very differently: Patients with the dysplastic subtype have low blood counts and their natural history and clinical problems related to marrow failure are more similar to patients with MDS; those with the proliferative subtype have high blood counts and often have constitutional symptoms or symptoms related to organomegaly. Patients with proliferative forms of the disease also have shorter survival and a higher risk of transformation to AML.

How Is CMML Treated?

There is only one curative treatment for CMML: allogenic HCT. Unfortunately, only a minority of CMML patients will qualify for the procedure.(³)

Complicating matters further, there are no studies that define when a transplant is the most appropriate option for CMML. Dr. Padron recommends that all patients with high-risk disease who are young and fit enough to be considered transplant candidates should be referred for consideration of an HCT.

Two other treatments are approved for CMML, both hypomethylating agents approved for MDS for which the FDA indication included CMML: azacitidine and decitabine. However, the pivotal trials included few patients with CMML, and response rates are low, especially in proliferative forms of the disease.

“There’s an injustice that has been done to this disease, going back almost a decade,” Dr. Patnaik said, referring to the WHO’s 2008 classification, which introduced the MDS/MPN category of diseases that displayed proliferative and dysplastic characteristics.

“Essentially all the trials that included patients with CMML used disease response criteria designed for MDS,” he explained. “There is clear evidence that [treatment with hypomethylating agents] does not alter the disease biology. In fact, in Europe, if a patient has proliferative CMML, hematologists can’t even use these drugs.”

Instead, doctors tend to treat patients with drugs that target specific symptoms of CMML, such as cytopenias, splenomegaly, and infections with transfusions, blood cell growth factors, and antibiotics. While these can improve patients’ quality of life, Eric Solary, MD, and Raphael Itzykson, MD, wrote in Blood, ”they barely modify disease evolution. … Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.”⁽⁴⁾

How Do We Know if a Treatment Is Working?

The higher prevalence of MDS had a negative effect on CMML clinical trials. “For a long time, the community was so interested in MDS that CMML-specific trials were almost absent,” Dr. Patnaik added. For example, he said, drug studies can enrol 400 patients with MDS, and 10 with CMML.

A major impediment to conducting CMML-specific drug trials has been a lack of uniform response criteria. Without these, it is extremely difficult to prove to regulatory agencies that a drug is working, even if a doctor can tell a patient is doing better. This decreases the likelihood of trials being supported or even considered.

“One of the difficulties in trying to understand how patients with different types of CMML respond to different therapies is that we never had [disease-specific] response criteria at all,” said Michael Savona, MD, a hematologist at Vanderbilt University in Nashville, Tennessee. “When we go to different trial sponsors to try to access new drugs, the most common response we get is, ‘Well, how do you know if it’s working?’ And, to be honest, we don’t have a very good answer.”

Defining response criteria is a challenge because the natural history and prognosis of CMML are poorly understood. There are about 10 prognostic scoring systems that have been proposed for CMML, explained Dr. Padron, adding that “there are no good data telling us when the best timing is for transplant.”

To fill in the knowledge gaps, Dr. Padron and colleagues have launched a project to sequence nearly 1,000 patients with CMML both before and after treatment “to see whether we can confirm what the prognostic mutations are and try to answer that question of which prognostic scoring system we should be using.”

In 2015, Drs. Savona and Padron were part of an international working group that published a proposal of uniform response criteria for CMML, which they hope will be independently validated and refined over time.⁽⁵⁾

“The FDA is quite keen on quality-of-life–associated response elements, and my sense is that if we can improve some of these quality-of-life metrics, specifically how patients are feeling and their spleen size, then that will translate to improved survival,” said Dr. Savona, who was first author on the response criteria paper. The proposal included criteria for measuring improvements in blood counts and reduction in myeloblasts, similar to MDS, but also meaningful reductions in spleen size and clinical symptoms.(5)

At the end of 2018, the European Hematology Association and the European LeukemiaNet released new guidelines for CMML diagnosis and management that update and revise criteria put forth by the MDS International Working Group (IWG) in 2000 and 2006.⁽⁶⁾

“While response to treatment can be evaluated by IWG 2006 criteria in [dysplastic] CMML, recently proposed ad hoc MDS/MPN criteria should be preferably adopted,” the guideline panel wrote. “With respect to pivotal phase III clinical trials, we recommend robust primary endpoints such as overall survival, progression-free survival, or event-free survival, and incorporation of the MDS/MPN criteria as secondary endpoints.”

Where to Next?

While the recently proposed international response criteria have increased interest in studying and developing treatments for CMML, researchers still have a long way to go. The patient population is exceptionally heterogeneous and the disease relatively rare, making clinical validation a challenge.

Studying this rare disease might require new trial designs. Dr. Savona is the principal investigator of the ABNL-MARRO study, an initiative from the MDS/MPN IWG and Vanderbilt University Medical Center in which Drs. Patnaik, Padron, Solary, and Itzykson are also involved.⁽⁷⁾ ABNL-MARRO, or “A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes,” will enrol patients with MDS/MPN overlap syndromes in the U.S. and several European countries.

The basket design allows new compounds and therapy combinations to be introduced easily among MDS/MPN IWG clinical sites where patients with MDS/MPN are treated. Researchers also will study the biology and pathophysiology of the diseases to identify potential markers of severity, prognosis, and response.

“We’re proud of this study because it is going to open across the U.S. and Europe with the same protocol,” said Dr. Savona. “It’s been the challenge of my career to try to operationalize something across different countries like this.” —By Emma Yasinski

References

1. 1. American Cancer Society. “What Are the Key Statistics About Chronic Myelomonocytic Leukemia?” Accessed April 10, 2019, from https://www.cancer.org/cancer/chronic-myelomonocytic-leukemia/about/key-statistics.html.
   2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-405.
   3. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Blood. 2010;116:4762-70.
   4. Solary E, Itzykson R. How I treat chronic myelomonocytic leukemia. Blood. 2017;130:126-36.
   5. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125:1857-65.
   6. Itzykson R, Fenaux P, Bowen D, et al. Diagnosis and treatment of chronic myelomonocytic leukemias in adults. HemaSphere. 2018;2:e150.
   7. ABNL MARRO. Accessed April 10, 2019, from https://abnlmarro.org/.

New diagnoses of IPSS INT-2/High patients

• Almost all patients will become neutropenic during the first 1-3 cycles of azacitidine therapy
• Therefore consider whether a delay in initiating azacitidine could be acceptable to the patient and clinician. In the AZA-001 registration study, only 52% patients were treated within one year of original diagnosis (which for some, may have been lower-risk). Patients’ management should be assessed by the MDT on an individual basis and then discussed with the patient. Delay may be acceptable for the following groups but this is not an exhaustive list:
  • Patients with relatively well preserved blood counts (e.g. neutrophils >1)
  • Patients with stable blood counts for the preceding 3 months and neutrophils > 1
  • Patients with lower blast count (<10%)
  • Patients lacking good-risk ‘AML’ genetic / genomic characteristics
• If azacitidine therapy deemed immediately necessary, consider using G-CSF and / or antibiotic prophylaxis through cycles 1 & 2 in order to try to prevent hospitalisation with neutropenic sepsis.
  • Where feasible and subject to local guidelines for home administration of azacitidine, consider alternative models of care to minimise hospital attendance for azacitidine injections
  • Blood count monitoring should not be reduced, continuing per local guidelines, but samples taken in the patient’s home where possible and attendance to hospital following, based on local blood product transfusion policy.

Patients already on azacitidine

• Beyond cycle 3, if patients are deemed to be having clinical benefit, consider increasing interval between cycles to 6 weeks, or continuing 4-weekly but reduce to 5 days azacitidine per cycle. Note that there is no trial evidence for a switch from 4-weekly to 6-weekly intervals, but there is some (under-powered) randomised trial evidence that 5-day azacitidine cycles may be less efficacious than 7-day cycles.