“The Leukemia You Want to Have”

Shelly was living in Bogota, Colombia, when she first realized something was wrong. She was tired and out of breath. Living at 2,600 meters of elevation can do that – but she had given her body plenty of time to adapt. Heart issues ran in the family, so she wondered if that might be causing her problems. Eventually, her symptoms became so strong that she moved back to the US to pursue diagnosis.

As the tests were being done, Shelly found that her skin was covered in bruises. “Blooms,” she calls them. “Like I’d been in a car accident every day.” She knew then that it wasn’t a heart issue, but she never suspected cancer. Heart attacks and strokes ran in her family, but not malignancies. In 2014, a doctor handed her a printout from a hairy cell leukemia website. Shelly could hear herself being asked questions, but all she could say was, “My life has changed.” The doctor nodded.

Keen to research her new diagnosis, Shelly soon discovered a trial at the National Institute of Health. By February 2015, she’d started treatment. Shelly attended every appointment, every test, and every available treatment on her own. Things went well. They said she “sailed” through it. Eventually, doctors told her that her bloods had been in decline all the way back in 2008. “They said yes, I could have had it for 20 years.” Today, she gets bouts of fatigue and struggles with her memory.

A hairy situation
 

Hairy cell leukemia (HCL) is a rare form of chronic leukemia that makes up about one in every 50 leukemia cases. The name comes from the appearance of a patient’s cells under a microscope; after they undergo malignant transformation, they present with a fuzzy, wispy aura. Many members of the public are completely unaware of chronic leukemias and, when faced with diagnosis, are understandably confused and frightened. One response to this confusion is the Hairy Cell Leukemia Support Group, a Facebook community with 1,700 members (not bad considering that there are roughly 6,000 HCL cases in the US). Shelly, one of the group’s admins, spoke with me about some of the struggles patients face during the diagnostic process.

“HCL can be hard to spot,” she tells me. “It’s long-term; most people have it for years before it’s discovered. Some of us have big symptoms; others don’t. The biggest problem we have is the lack of knowledge in some physicians.”

She adds, “We don’t expect every doctor to be up to date on every disease all the time. But some docs don’t bother to look into the most recent medical info when a new patient presents with HCL. They don’t know how to treat it – advising a second round of treatment too soon after the first, not wanting to try rituxan with cladribine, and so on. The chemo is known to react with certain drugs – sulfas and allopurinols – but those drugs still get prescribed as preventatives, even in cases when they may not be needed.”

Shelly urges patients to talk to their doctors and to reach out to specialists at HCL Centers of Excellence, which can be found on the Hairy Cell Leukemia Foundation website. “The members of the group are probably as informed as – if not more informed than – doctors who rarely see HCL. Some docs don’t even know the BRAF connection, which changes treatment plans. That’s kind of important.”

Although many practitioners try to maintain awareness of uncommon conditions, HCL presents an additional challenge in that the science of the disease has changed drastically in just a few decades. A generation ago, HCL was often considered a death sentence. But is that still true today?

A chronic curiosity
 

We spoke with Graeme Quest from the Hairy Cell Leukemia Foundation to find out more about the experiences of professionals treating patients with HCL. His passion for studying the disease is palpable and his answers highlight just how much our understanding of HCL has transformed over the last few decades.

How long have you been involved in HCL treatment? What inspired you to enter the field?

Seeing the unique appearance of hairy cells under the microscope during residency really struck me and made me wonder what made them so unique. I dove into a resident research project and learned more about their unique biology and the history of the disease – including the features that initially led us astray and suggested that they might have been leukemic reticuloendothelial cells!

Partway through my project, the initial report that found the BRAF V600E mutation present near-universally in classic HCL further fed my fascination. That paper really tied together the morphology and the molecular pathophysiology – and, with that, I was hooked!

For those who aren’t aware, what is HCL and how is it diagnosed?

Hairy cell leukemia is a mature B cell neoplasm with a particular predilection for the spleen and bone marrow. Incidental discovery through routine bloodwork or presentation of significant cytopenias in association with infection are the most common routes to diagnosis, though rare dramatic presentations with spontaneous splenic rupture are unforgettable. Often, the first clue is the presence of unusual monocytoid lymphocytes on peripheral blood review in conjunction with cytopenias – particularly monocytopenia. Flow cytometry of the peripheral blood is typically the next step toward diagnosis; the characteristic coexpression of CD11c, CD25, and CD103 with unusually bright CD20, CD22, and CD200 on mature B cells clinches the diagnosis in most cases.

Bone marrow evaluation also plays a key role in assessing the extent of marrow involvement. Aspirates are often aparticulate, but trephine biopsy demonstrates a classic interstitial infiltration pattern of the monocytoid B cells with a “honeycomb” appearance, often with mild associated reticulin fibrosis. Finally, immunohistochemistry or molecular testing for the BRAF V600E mutation should be performed in all cases. The presence of the mutation is highly specific and confirmatory for the diagnosis among B cell neoplasias, whereas its absence may reflect a rare subset of classical HCL that tends to demonstrate a worse prognosis. This could be another splenic lymphoma masquerading as classic HCL, such as splenic diffuse red pulp lymphoma, splenic marginal zone lymphoma, or the entity formerly known as variant hairy cell leukemia (now splenic B cell lymphoma/leukemia with prominent nucleoli – quite a mouthful!).

What is unique about HCL compared with other blood cancers?

So many things! From its strikingly villous “hairy” cytomorphology and “honeycomb” histomorphology to its substitution of splenic littoral cells with “blood lakes” in the spleen. It’s certainly eye-catching to look at! Hairy cells also seem to want to masquerade as monocytes and actively phagocytose bacterial and yeast particles… and the BRAF V600E mutation can also be seen in some histiocytic neoplasms. Finally, HCL shows a marked gender imbalance that we don’t understand; most populations show a ~5:1 bias toward males. That said, the diagnosis should never be overlooked in women, who may be younger or have less typical presentations (associated with adenopathy).

The treatment of classical HCL is also unique – it is exquisitely sensitive to single-agent purine nucleoside analogues (such as pentostatin or cladribine), with clinical trials of these agents really hitting a home run. After even one week of treatment with cladribine, approximately 50 percent of patients will remain in hematologic remission for over 15 years! A new generation of targeted BRAF and MEK inhibitor therapies are transforming care in people who have infections or are otherwise too frail for cytotoxic chemotherapy. For a rare disease, there has been a lot of transformative science and therapeutic progress – constant and consistent over the last 30 years!

Is there anything (good or bad) that catches your eye when you look at results?

I’m very interested in rare variants with atypical phenotypes. We usually expect HCL to be a CD5- CD10- B cell, but many are surprised to learn that CD10+ variants aren’t all that unusual (~8 percent of cases), whereas CD5+ variants are rarer (~2 percent of cases). Though these may go unrecognized or be confused with non-nodal leukemia or mantle cell lymphoma, I’ve also seen cases that break other immunophenotypic “rules,” such as missing CD25 or CD103 expression. Presentations with unusual autoimmune features, adenopathy, or bone lesions are also not well understood in frequency or in biology. Given HCL’s rarity, it is difficult to study whether these features have prognostic significance, which is why the Hairy Cell Leukemia Foundation’s work (and its international Patient Registry) is so important!

What has changed most for HCL during your career?

The discovery of new diagnostic markers (such as annexin A1 and CD123) and new treatment options such as BRAF purine nucleoside analogues, the addition of rituximab, and now trials demonstrating the effectiveness of BRAF (+/- MEK) inhibitors (+/- anti-CD20 antibodies) and moxetumomab pasudotox.

Perhaps the most inspiring, though, is the formation of the Hairy Cell Leukemia Foundation – an international collaboration of individuals diagnosed with HCL, their loved ones, and scientific and medical experts to make sure that we continue the tremendous progress in understanding this disease and working toward a definitive cure.

Is it true that HCL patients used to have a short life expectancy after diagnosis – and, if so, is that still the case?

It’s true; life expectancy for patients with HCL used to be very short and splenectomy was the only real treatment option for a long time. Interferon alpha helped, but things really changed with the advent of purine nucleoside analogues in the early 1990s. So much so that many clinicians falsely believe we’ve “solved” HCL. There is a degree of truth to that, but even though about half of patients remain in remission for over 15 years, the other half still experience one or more relapses in their lifetime – particularly those diagnosed before age 40. Continued progress on new therapies for individuals with relapsed and refractory disease now allow a normal life expectancy for most patients. It has certainly been an honor and a privilege to meet and collaborate with many people affected by HCL through the Foundation and regional forums.

What lies ahead for HCL research?

A lot! It’s still a bit of a mystery where hairy cells come from – they are memory B cells, but don’t seem to pass through germinal centers or gain CD27 like most memory B cells. We know that the BRAF V600E mutation is found in the early hematopoietic stem cells in HCL and some histiocytic neoplasms, though the two virtually never coexist or occur sequentially – so there is some added mystery in what commits these stem cells to their path. We really don’t understand why the gender bias in HCL exists, including what (if any) role sex hormones or other factors may play. The evaluation of minimal/measurable residual disease is a hot topic in many areas of hematology and no less so in HCL, though it seems much more complicated. We’ve come an incredible way in understanding and treating the disease, but it’s clear that there is still a lot we don’t know!

Is there anything you’re particularly excited about?

The HCL Foundation Patient Registry! I think we are going to get a much fuller view of the variation in presentations, symptoms, and prognostic features – particularly those rare presentations of an already rare disease.

I could talk about HCL for days, but I’ll leave you with one more mention of the HCL Foundation – an international consortium of HCL patients, families, scientists, pathologists, oncologists, and hematologists. It’s a wonderful resource for diagnosing and treating physicians faced with unusual clinical scenarios, so don’t hesitate to reach out. We are here to help!

A call to practitioners…
 

We asked Shelly about the interactions she has had with pathologists and what she might say to laboratory medicine professionals today.

“Almost every doctor tells newly diagnosed patients that this is the leukemia you want to have if you have to have one. In the long run, we’d like to hear that – but right after you’ve been told you have cancer isn’t necessarily the best time. Is there really such a thing as a ‘better’ cancer to have?”

She continues, “When I meet a new doctor, I always want to know their background. How did they decide to go into this field? I’d ask what they think is most unique about HCL compared with other blood cancers. What makes their eyes pop (good or bad) when they look at results under a scope or on paper? I’d also thank them for their contribution to the field of medicine. It wasn’t until interferon alpha came out that we had any real treatments at all. HCL was 100 percent fatal until then, with a five-year life expectancy at best. Researchers and doctors have been saving lives, so the most important thing I’d like to say is thank you – from all of us.”

Shelly Battista is co-admin of the Hairy Cell Leukemia Support Group.

Graeme Quest is Hematopathologist and Director of Transfusion Medicine and Immunology at Kingston General Hospital; and Associate Professor and Director of Immunology in the Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada