New Initiative Seeks to Jump-start Era of CMML Care

Chronic myelomonocytic leukemia (CMML) has historically lingered in the penumbra of more prominent disorders such as myelodysplastic and myeloproliferative neoplasms (MDS/MPN). However, a new collaborative effort between CMML researchers and The Leukemia & Lymphoma Society (LLS) hopes to jump-start patient treatment and advance scientific understanding of this rare disease.

Central to this collaborative effort is a clinical trial network, an initiative currently in development, explained Lee Greenberger, PhD, the Chief Scientific Officer at LLS.

“The hope is to enroll patients into trials in an accelerated way,” Dr. Greenberger said. “LLS could help recruit those patients because we have clinical trial support services and are building a clinical trial network for CMML patients.”

With an estimated prevalence rate of four per 100,000 people per year,¹ CMML has been underrepresented both in clinical trials and drug development.²

“It definitely is a rare disease and a great unmet need because the disease over time has spent most of its life in the shadow of MDS or MPN,” said Mrinal Patnaik, MBBS, a physician-scientist at the Mayo Clinic in Rochester, Minnesota. “The hope is that with LLS being involved, it will give us all the infrastructure, impetus, and support to continually evolve this into something more definitive than where it is now.”

Additionally, strict criteria for trial inclusion often exclude patients with CMML from participating in the already limited studies available, Dr. Greenberger explained.

“These patients have to be placed in clinical trials,” he said. “However, not all patients are going to want to—or be available to—participate in clinical trials, or even meet all the inclusion criteria.”

Addressing this issue, Guillermo Montalban-Bravo, MD, an Assistant Professor at the University of Texas MD Anderson Cancer Center who is among the group of leading researchers contacted by LLS to help set up the network, pointed out only a handful of institutions, including his own, have CMML-specific studies.

“Right now, there are only a few major academic centers that focus on CMML in the United States or elsewhere,” Dr. Montalban-Bravo said. “The initiative of LLS, in part, was to allow multiple institutions, or particularly smaller institutions, to more easily grant patients access to these CMML-specific trials.”

The lack of CMML-specific trials also hinders the identification of effective treatments for these patients, explained Dr. Montalban-Bravo.

“It’s going to be difficult to identify novel, effective drugs for these patients if we don’t develop clinical trials that specifically address them,” he said.

Becoming Its Own Entity

From a historical perspective, the current lack of CMML-specific clinical trials can be traced back to the difficulty in accurately diagnosing CMML in the first place. The lack of detailed genetic mutation data and the disease’s overlapping features with MDS and MPN led it to be characterized as belonging to one group or the other depending on attributes such as the patient’s bone marrow characteristics and disease behavior.³

“The real prevalence of the disease is not very well described,” said Douglas Tremblay, MD, a hematologist at the Icahn School at Mount Sinai. “It’s an inherently biologically diverse population of patients, and we frequently lump them together, but there’s many different types of CMML. It also has been challenging to understand the optimal treatment for these patients because they’re often lumped in with either MPN or MDS, and that makes it difficult to design therapeutic strategies for them.”

Traditionally, CMML was grouped together with MDS when it presented with certain blood and bone marrow characteristics. Conversely, when CMML exhibited more proliferative traits, it was sometimes aligned more closely with myeloproliferative disorders, Dr. Tremblay explained.

“There’s a lot of overlap between these diseases: patients with myelofibrosis may have monocytosis and patients with CMML may have bone marrow fibrosis, and so they may be classified as myelofibrosis but may actually have a disease more accurately characterized as CMML,” he said.

As researchers began to discover CMML-specific mutations and disease markers, the World Health Organization (WHO) adapted its classification criteria, acknowledging CMML as a distinct disease entity. Since that time, and especially in the past decade, there has been fresh momentum in the international medical community to develop specific research in CMML and other MDS-MPN overlap syndromes, Dr. Montalban-Bravo said.

Recently, the WHO further adjusted its classification criteria for CMML, making them more inclusive and broadening the recognition of patients who may have previously been categorized as having MDS, according to Dr. Montalban-Bravo.

“This is a field that is ever-changing based on how the research moves forward and what we identify,” he said. “Certainly, the scenario is very different today than it was 15 years ago in terms of recognition of and research in these specific entities, and then also the development of clinical trials and novel drugs and treatment for these patients.”

Yet, this progress has not been without its setbacks. Dr. Patnaik expressed concern that valuable time has been lost because CMML was historically “lumped under MDS,” and in particular because CMML response criteria were based on those used for MDS, which failed to fully encompass the intricacies of CMML.

The delay has had implications for treatment, as the only drugs approved by the US Food and Drug Administration (FDA) for CMML are azacitidine, which was approved in 2004, and decitabine,⁴ including a fixed-dose oral combination of decitabine and cedazuridine approved in July 2020.^5-7

“The [azacitidine] approval came off two studies, one in the United States and one in Europe, which were largely done for MDS. They had a handful of CMML patients enrolled, and all of them had dysplastic CMML,” he explained. “It is a proper approval, but you can question whether it is valid for the myeloproliferative CMML variants where current data suggest that they are not really effective.”

Dr. Patnaik also pointed out a more cautious approach in Europe, where azacitidine is only approved for myelodysplastic CMML when patients have an increased number of blasts, indicating that “the European counterpart of the FDA has been more restrictive than the US FDA in drug approvals for CMML.”

The slow pace of the uncoupling of CMML from MDS has impeded the discovery of novel treatments and the establishment of CMML-specific clinical trials, he added.

“We have the response criteria, and we have the FDA’s attention that this is a unique entity, but now we need to bring the therapies,” Dr. Patnaik said. “The underlying problem is that there haven’t been enough trials conducted. This has resulted in limited first-line options and no FDA/[European Medicines Agency]-approved second-line options for patients with CMML.”

Advances Lag in CMML

While CMML is rare, it is not rarer than other blood cancers, according to Eric Padron, MD, who is the Scientific Director in the Division of Malignant Hematology at the Moffitt Cancer Center in Tampa, Florida.

“I certainly don’t view it as more rare, complicated, or difficult to diagnose than any other blood cancer,” he said. “So why aren’t there advances in CMML like there are in the other blood cancers? It can’t be just because of rarity.”

Dr. Padron, who is part of the LLS initiative and has worked in CMML for the length of his career, believes that the slow pace of advancement in CMML might be tied to the lack of CMML-specific drug approvals by the FDA and other regulatory bodies.

A drug approval specific to CMML would catalyze a surge of interest in the hematology-oncology community, Dr. Padron believes. Currently, the absence of such an approval may lead some clinicians to view treatment as merely theoretical, particularly because patients with CMML have historically received the same protocols as those with MDS.

“When a drug approval happens, there’s a rush of interest; diagnoses become better as people begin to care more,” Dr. Padron said. “That’s the whole premise behind the clinical trial network; in our view, getting a drug approved by the FDA for CMML specifically will lead to a lot of other downstream things to help take care of these patients.”

Dr. Patnaik agreed that new drug approvals are essential and called on the research community to drive development by identifying mechanisms and targets.

“The onus lies on us to bring drugs to the FDA and say, ‘These are things that we think work.’ It’s up to us, the physician-scientist community, to find rationally derived therapeutic targets,” Dr. Patnaik said.

Nonuniform Nature of CMML

Currently, allogeneic hematopoietic stem cell transplantation is the only curative treatment for these patients, but the treatment is associated with significant morbidity and mortality.^8,9 Other drugs, including the recombinant fusion protein luspatercept¹⁰and the Janus kinase inhibitor ruxolitinib¹¹ have been repurposed from MDS or MPN to treat CMML.

“There are patients who may not need intervention, and there are patients who should go to transplant relatively fast,” Dr. Montalban-Bravo said. “There are patients who have a very benign disorder, where the disease is not defined by having any kind of high-risk features, but there are other patients in whom the disease is very aggressive, and it can behave as severely as AML.”

CMML can progress to AML,¹¹ particularly in high-risk patients, where the progression to more aggressive leukemia is common, Dr. Tremblay noted.

“Many CMML patients also have a subtype of CMML-2 (a blast percentage of 10% to 19%), and while those patients are called CMML, they really have a disease that is biologically similar to AML,” he said.

This progression of CMML to AML, especially in high-risk patients, sets a challenging backdrop for treatment. In response, Dr. Tremblay and colleagues presented a study on the efficacy of venetoclax with hypomethylating agents (HMAs) in CMML at the 65th American Society of Hematology Annual Meeting & Exposition, linking CMML treatment strategies to approaches validated in AML.12

Venetoclax is an approved therapy for AML and has been shown to improve survival in that disease and deliver an increase in response rates.¹³

“Because of that, there’s been a little bit of creep into different related myeloid diseases, especially MDS, where there is now a phase III trial evaluating venetoclax plus azacitidine in MDS,” Dr. Tremblay said, adding that “patients with CMML are really excluded from that phase III MDS experience.”

The researchers reported in their study that even though higher response rates were reported, that didn’t translate to survival.

“While HMA plus venetoclax in both CMML and CMML blast transformation induced higher response rates, it did not translate into survival differences,” Dr. Tremblay said. “In the CMML population there was prolongation and improvement in leukemia-free survival. While there is activity in terms of response rates, it doesn’t translate into survival.”

While he thinks the results were disappointing in terms of prolonging survival, he noted another analysis part of the study looked promising for an HMA plus venetoclax combination in bridging patients.

“We also looked at a population of patients who were treated with an HMA first and then had venetoclax added on, and in those patients, in both CMML and CMML after blast transformation, about 25% of them were able to transition to transplant,” he said, adding “I do still think there’s probably a role for the combination in treating high-risk patients who are eligible for transplant.”

No Funding

While there are phase I and II trials available at centers such as MD Anderson, Moffitt, and the Mayo Clinic, there are no phase III studies in CMML underway, mainly due to a lack of funding and the institutional scale that would be required.

“It is challenging to develop a phase III study without it being a large, multicenter, international, cooperative study,” Dr. Montalban-Bravo said.

Dr. Tremblay singled out support from the pharmaceutical industry as the missing link in the transition to phase III.

“In order to do phase III trials in this disease, there has to be input and sponsorship from our pharmaceutical partners to really invest in this space because there is a huge unmet need,” he said.

However, support from organizations like LLS and the demonstration of successful FDA approvals have the potential to alter the industry’s perspective, according to Dr. Padron.

“There’s a misconception in the industry. They don’t believe that the economics make sense for a phase III trial because the payoff isn’t going to be high enough,” he said. “But with LLS being behind this initiative and then showing, ‘Hey, this is what happens when you get an FDA-approved drug,’ I think it will change.”

That shift in perception might already be taking place: the FDA has been increasingly raising awareness about CMML and the need for clinical trials in the disease, Dr. Padron explained.

“I think the industry’s finally coming around to the notion that CMML is a huge unmet need,” he said.

This is the moment for organizations and funding bodies to acknowledge the need to advance CMML research and for investigators to put their heads together to find solutions, Dr. Patnaik said.

“People like myself and Eric Padron have been fighting this battle for the last decade,” he said. “Rare diseases are not rare for the people affected by them. Just because it’s a rare disease doesn’t mean it shouldn’t get support.”

Leah Sherwood is the Managing Editor of Blood Cancers Today.

References

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11. Hunter AM, Newman H, Dezern AE, et al. Integrated human and murine clinical study establishes clinical efficacy of ruxolitinib in chronic myelomonocytic leukemia. Clin Cancer Res. 2021;27(22):6095-6105. doi:10.1158/1078-0432.CCR-21-0935
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13. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. FDA. October 16, 2020. Accessed March 4, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia