TEMPI Syndrome: Researchers Call for Hematologists to Gather Around the Mystery

It began with an appeal. In 2008, David Sykes, MD, PhD, now an assistant professor at Harvard Medical School in Boston and then a chief resident in medicine at Massachusetts General Hospital, had a puzzling case regarding a patient who had traveled in search of a fourth opinion. The patient presented with marked erythrocytosis, elevated serum erythropoietin, and large perinephric fluid collections. Dr. Sykes found the case to be so interesting that he proposed it as a clinicopathological conference (CPC) to the New England Journal of Medicine. At the end of the CPC, he asked readers to email him if they had seen anything similar.¹

Dr. Sykes almost immediately received two responses, one from California and one from Belgium, both sent by hematologists who were caring for similar patients.² These three patients, in addition to three more in the medical literature, meant that, in 2011, there were a total of six known patients with TEMPI syndrome. Dr. Sykes now knows of a total of 38 patients from 17 countries who have the diagnosis.

“This is the way it started, just with an appeal,” said Wilfried Schroyens, MD, PhD, professor emeritus at the Vaccine & Infectious Disease Institute at the University of Antwerp. “Has anyone else seen this?”

Dr. Schroyens was following a young woman in Antwerp with small dilated blood vessels near the surface of her skin. When she first presented, her hemoglobin was close to 20 g/dL. Dr. Schroyens assumed that she had JAK2-negative polycythemia vera and started treating her with phlebotomies. The treatment made her worse, and she complained that she could no longer bike up a hill. Dr. Schroyens then treated her unsuccessfully with anti-vascular endothelial growth factor-1 and then with thalidomide in the hope that the anti-vascular growth effect would be beneficial. Dr. Schroyens described this whole period as “just trial and error.” Over the years, as the patient’s disease progressed, her oxygen saturation decreased until she became confined to a wheelchair and required 24-hour supplemental oxygen.

“My patient was in need of treatment,” Dr. Schroyens emphasized. “She was not doing well.” Dr. Schroyens, Dr. Sykes, and Casey O’Connell, MD, associate professor in the Jane Anne Nohl Division of Hematology at the Keck School of Medicine at the University of Southern California, consulted with each other on their three similar patients.

What Is TEMPI Syndrome?

The ultra-rare multisystem TEMPI syndrome acquired its name from its unique constellation of clinical abnormalities. In 2016, the World Health Organization classified it as a plasma cell neoplasm with associated paraneoplastic syndromes. Each component of the acronym TEMPI reflects a distinctive aspect of the syndrome:

• Telangiectasias: The small dilated blood vessels can present near the surface of the skin, mucous membranes, and eyes. For reasons unknown, they appear only on the upper half of the body and seem to spare the lower extremities.
• Erythrocytosis: In TEMPI, the levels of serum erythropoietin may become as high as 8,000 mU/mL (median erythropoietin levels in TEMPI = 500 mU/mL). The levels do not appear to correlate with hypoxemia.³ Erythrocytosis in TEMPI syndrome can lead to complications such as thrombosis and vascular events.
• Monoclonal gammopathy: Patients with TEMPI syndrome exhibit abnormal plasma cells in their bone marrow, which results in the production of monoclonal antibodies. For most patients, the plasma cell burden is generally at the level of monoclonal gammopathy of uncertain significance (MGUS; serum M-spike <3 g/dL and <10% clonal marrow plasma cells), although the burden may increase over time.³
• Perinephric fluid collections: Clinicians often discover these fluid accumulations surrounding the kidneys incidentally during imaging studies. Dr. Schroyens explained that as fluid accumulates, it can put pressure on the kidney and jeopardize kidney function.
• Intrapulmonary shunting: Newly formed blood vessels in the lungs cause venous blood to immediately mix with arterial blood without oxygenation in the lungs, resulting in decreased oxygen levels in the blood. Dr. Schroyens and others suspect that the same process underlies telangiectasia formation and microscopic intrapulmonary shunting.

Although almost all patients manifest telangiectasias, erythrocytosis, and monoclonal gammopathies, perinephric fluid collection and intrapulmonary shunting are not always present. Other less predominant clinical features include venous thrombosis, ascites, and pleural effusions. Clinicians in China described one patient with polyserosal effusions, a history of abdominal distension, and dyspnea.⁴ In their case series of three patients, the authors described additional distinct presenting symptoms: asymptomatic polycythemia in the first patient, skin pigmentation and abdominal distension in the second, and dyspnea in the third.

TEMPI syndrome is named for its unique combination of
clinical abnormalities.

How Is TEMPI Syndrome Diagnosed?

TEMPI syndrome belongs to the realm of exceedingly rare conditions. While sporadic cases have been reported in various regions worldwide with no obvious geographic pattern, the exact prevalence of the disorder in the U.S. and globally remains uncertain. The disorder appears to affect individuals across a wide age range, although it has been predominantly reported in adults in their 30s and 40s. There is no evidence to suggest a gender bias in TEMPI syndrome. Given the rarity of TEMPI syndrome, patients are often misdiagnosed or have a delayed diagnosis. Dr. Schroyens said clinicians should suspect TEMPI syndrome if an erythrocytosis is accompanied by an unexplained high erythropoietin value and telangiectasias.

Hematologists may encounter patients with TEMPI syndrome when investigating unexplained erythrocytosis or monoclonal gammopathies. Additionally, patients with TEMPI syndrome may develop complications, such as thrombotic events, for which hematologists play a crucial role in management.

Monoclonal gammopathies, a hallmark feature of TEMPI syndrome, can be further investigated with a bone marrow biopsy. While patients with multiple myeloma typically have a higher percentage of plasma cells, patients with TEMPI syndrome do not. In the case of a patient with longstanding and unexplained erythrocytosis with the combination of an elevated erythropoietin and monoclonal gammopathy, clinicians should perform a careful examination for telangiectasias and perform CT scans or ultrasounds to evaluate for perinephric fluid collections.⁵ Intrapulmonary shunting can be measured by contrast echocardiography and quantified by a technetium (Tc-99m) macro-aggregated albumin nuclear scan. Dr. Schroyens noted that not all patients experience perinephric fluid or intrapulmonary shunting at diagnosis, and he suspects that these symptoms are more common later in the disease.

Treatment Approaches

Because treatment for TEMPI syndrome differs from that for polycythemia vera, experts emphasize the importance of distinguishing between the two.³ There are currently no dedicated treatment guidelines for TEMPI syndrome and no prognostic markers.⁴ The current recommendation is that personalized regimens should be chosen for each patient with TEMPI syndrome, and patients should be carefully monitored for their response.

“Everything that decreases the level of monoclonal antibody seems to work,” Dr. Schroyens said, explaining that his patient received remarkable clinical benefit following treatment with bortezomib.⁶ The patient, 48 years old at the time, received a total of eight cycles of intravenous bortezomib (four doses of 1.3 mg per square meter of body surface area). She had a dramatic response to the proteosome inhibitor; her telangiectasia disappeared, her perinephric fluid collections disappeared, and her serum levels of erythropoietin decreased from 6,400 mIU/mL to 19 mIU/mL. “She got better,” Dr. Schroyens said, “and within six months she was bicycling again.”

The patient’s response led the investigators to hypothesize that the abnormal plasma cell clone and monoclonal antibody were the likely cause of TEMPI syndrome. “In the TEMPI community, it is accepted that the monoclonal antibody plays an essential role,” Dr. Schroyens said. He explained that other successful approaches to reducing the levels of the monoclonal antibody include treatment with daratumumab or a hematopoietic cell transplant. Bortezomib and daratumumab have acceptable side effect profiles, Dr. Schroyens said, and many of the known 38 patients with TEMPI syndrome have received these treatments.^6,7

In the case of Dr. Schroyens’ patient, the treatment response lasted only five years. Unfortunately, for patients in Europe and elsewhere around the world, Dr. Schroyens said, it can be difficult to obtain access to medicines or reimbursement for the medicines that are necessary to save these patients’ lives. For example, he would now like to treat his patient with a bispecific monoclonal antibody approved for the treatment of multiple myeloma but has been unable to get reimbursement.

Next Steps

Drs. Sykes and Schroyens thus make a second call to action and ask their fellow hematologists to respond with patients and patient samples. The communal effort is needed to save these patients’ lives and shed light on the target of the monoclonal antibody that is somehow able to increase erythropoietin levels so dramatically. “It still remains a mystery as to what causes TEMPI,” Dr. Sykes said. “If we are going to make progress, we have to join together on this.”

Dr. Schroyens noted that new research coming out of China has identified the IRF4 gene, rearrangements of which are common in patients with myeloma, as a causative agent in TEMPI syndrome.⁸ “I have some questions about their results,” Dr. Schroyens said. In particular, he questions whether there is a causal relationship, given the fact that the group based their conclusions on data from a single patient. Dr. Schroyens’ caution stems from experience; he and Dr. Sykes have found promising leads, only to have them evaporate when applied to more patients. As of now, they have yet to find a conclusive causative agent.

Dr. Sykes and collaborators in Pittsburgh and elsewhere have published the results of comprehensive next-generation sequencing (NGS) testing of bone marrow material from a 53-year-old male with TEMPI syndrome.³ The NGS panel covered 1,425 known cancer-related genes, including JAK2, and found no pathogenic variants and no structural or numerical cytogenetic abnormalities. Such findings are consistent with previous studies that have been unable to identify mutations and cytogenetic abnormalities associated with MGUS or symptomatic plasma cell myeloma.

Drs. Schroyens and Sykes together have extensive samples from 10 patients. They have studied the patients’ plasma cells in detail and performed transcriptomic analysis and whole-exome sequencing. They have also evaluated the cytokines in several patients without finding a clear link between cytokine production and TEMPI syndrome. In contrast, other investigators have reported preliminary results suggesting that increased secretion of macrophage migration inhibitory factor may increase vascular endothelial growth factor and hypoxia-inducible factor in TEMPI syndrome.⁹

Both Drs. Sykes and Schroyens see the identification of the antigenic targets of the monoclonal antibody as a critical next step. “How can a monoclonal antibody trigger the production of red blood cells?” Dr. Schroyens said. They have collaborated with Jens Wrammert, PhD, associate professor in the Department of Microbiology and Immunology at Emory University School of Medicine in Atlanta, to clone the monoclonal antibodies from six patients and produce the antibodies in vitro. Although these recombinant patient antibodies will be powerful research tools for in vitro and in vivo testing, more patient samples will be needed to continue building the toolkit to ultimately understand what is driving the symptoms of TEMPI syndrome.

The investigators appeal to the hematology community to create a coordinated international effort to solve the problem of TEMPI syndrome. Such an effort should ultimately include the creation of an international registry to facilitate the collection and storage of research samples across the globe. Dr. Schroyens pointed to the large implications for the research, explaining that while hematologists typically see low-level monoclonal antibodies as insignificant, TEMPI syndrome suggests otherwise. “We see that monoclonal gammopathies are responsible for more diseases and are not just innocent bystanders,” he said. Future research may yield insights into genetic predispositions or environmental influences that make certain patients vulnerable to monoclonal antibodies.

Drs. Sykes and Schroyens ask that their colleagues reach out when they identify these ultra-rare patients, both for the purpose of treatment recommendations and collection of patient samples. Dr. Sykes hopes it may one day be possible to leverage what he describes as “a crazy mistake of nature” into a real advancement of erythropoietin biology. After all, he said, tens of millions of people lack erythropoietin. What if the TEMPI monoclonal antibody can be repurposed into a tool for erythropoietin production in patients with anemia? Identifying the pathophysiology of this mysterious syndrome has the potential to benefit many more patients than just the 38 with TEMPI syndrome.

Drs. Sykes and Schroyens encourage any readers with patients with TEMPI syndrome or related symptoms to reach out and connect with them at the following email addresses:

• [email protected]
• [email protected]

References

1. Bazari H, Attar EC, Dahl DM, et al. Case records of the Massachusetts General Hospital. Case 23-2010 — a 49-year-old man with erythrocytosis, perinephric fluid collections, and renal failure. N Engl J Med. 2010;363(5): 463-475.
2. Sykes DB, Schroyens W, O’Connell C. The TEMPI syndrome – a novel multi-system disease. N Engl J Med. 2011;365(5):475-477.
3. Nunes Rosado FG, Lekovic D, Gagan J, et al. Comprehensive next-generation sequencing testing in a patient with TEMPI syndrome. Lab Med. 2023;54(5):546-549.
4. Xu ZF, Ruan J, Chang L, et al. Case report: TEMPI syndrome: report of three cases and treatment follow-up. Front Oncol. 2022;12:949647.
5. Sykes DB, O’Connell C, Schroyens W. The TEMPI syndrome. Blood. 2020;135(15):1199-1203.
6. Schroyens W, O’Connell C, Sykes DB. Complete and partial responses of the TEMPI syndrome to bortezomib. N Engl J Med. 2012;367(8):778-780.
7. Sykes SB, Schroyens W. Complete responses in the TEMPI syndrome after treatment with daratumumab. N Engl J Med. 2012;378(23):2240-2242.
8. Liu J, Zhang Z, Xu W, et al. IRF4-BLOC1S5, the first genomic fusion gene identified in the TEMPI syndrome. Blood. 2023;142(Suppl 1):1923.
9. Sun, Xu, Zhang B, et al. Whole-genome sequencing suggests a role of MIF in the pathophysiology of TEMPI syndrome. Blood Adv. 2021;5(12):2563-2568.