The treatment of common hematological malignancies is based on reams of study data and years of physician experience with the diseases. But such information is often limited for rare, little-researched blood cancers like blastic plasmacytoid dendritic cell neoplasm (BPDCN). This situation may soon change, thanks to the discovery of a new molecular target, which has led to a spate of innovative treatment approaches and the first dedicated clinical trials for this uncommon malignancy.
“When I first became interested in BPDCN about 7 years ago, there was practically nothing on it, but now there’s an explosion of research going on,” said Naveen Pemmaraju, M.D., an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “A number of exciting and novel clinical trials and approaches are rapidly coming out for this disease, which previously had no available therapies.”
And these advances in BPDCN also have implications for related diseases.
A rare, aggressive disease
Although BPDCN has been long recognized as a distinct clinical entity, its name has changed frequently. Previously known as natural killer blastic cell lymphoma, CD4+ CD56+ hematodermic tumor, blastic natural killer lymphoma, and natural killer cell leukemia, among other names, BPDCN was given its current designation by the World Health Organization in 2008.
“BPDCN was once thought to be an exceedingly rare tumor. But now, with better pathology, classification, and recognition, it appears to be a bit more common than previously believed,” Dr. Pemmaraju said. To illustrate this point, he said, “This year, I’ve had one or two patients per month referred for BPDCN treatment. In contrast, our institution saw only approximately 26 confirmed BPDCN patients from 1998 to 2014.”
BPDCN is primarily a disease of the bone marrow and blood cells, but unlike most other leukemias, BPDCN can also affect the skin. “This is a predominant feature of the disease,” Dr. Pemmaraju said. BPDCN, which tends to occur in older men, can also affect the lymph nodes and has a predilection for the central nervous system and brain.
“BPDCN is also a startlingly aggressive disease, on the order of acute leukemias like acute myeloid leukemia [AML] and some high-risk acute lymphoblastic leukemias [ALLs],” Dr. Pemmaraju said. “We have patients who can go from presenting with skin-only disease to a terminal acute leukemic phase in a year or less.”
Owing to the rarity of BPDCN, there has been very little research into its treatment, which is largely borrowed from the other leukemias. Thus, patients with BPDCN typically receive a combination of AML and ALL treatments that may include multi-agent intensive chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or cyclophosphamide, vincristine, doxorubicin, and dexamethasone [hyperCVAD]), central nervous system prophylaxis, radiation therapy, and stem cell transplantation, along with skin treatment as needed.
“But even with those aggressive therapies, the median overall survival for BPDCN patients historically has been only 1–2 years,” Dr. Pemmaraju said. “This is unacceptable to us as providers and researchers.”
A new target in BPDCN
CD123 (also known as interleukin-3 receptor) is a cell-surface protein involved in the proliferation and differentiation of hematopoietic cells. Whereas normal hematopoietic cells have no or low CD123 expression, virtually all BPDCN cells overexpress CD123. This overexpression ramps up the production of BPDCN cells, enabling them to overcrowd normal, healthy cells.
“CD123 is so primitive in its expression that some researchers think that it is carried on leukemia stem cells, the early or primordial cells that may be predecessors to some of the cells that give rise to these cancers,” Dr. Pemmaraju said.
In addition to its overexpression in BPDCN, CD123 is overexpressed in a number of other hematological disorders—including AML, chronic myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia (CMML), and myeloproliferative neoplasms—albeit to a lesser extent than in BPDCN.
“CD123 is differentially expressed between leukemia cells and normal cells,” said Marina Konopleva, M.D., Ph.D., an associate professor in the Department of Leukemia. “This principle can be exploited to target the receptor and destroy leukemia cells without harming normal cells.”
The CD123-targeting agent furthest along for BPDCN treatment is SL-401, a recombinant fusion protein comprising a diphtheria toxin fused with interleukin-3. The drug’s origins can be traced to the work of Dr. Arthur Frankel, now at The University of Texas Southwestern Medical Center in Dallas.
The interleukin-3 domain of SL-401 binds to CD123 on the cancer cells, which then take up the entire molecule. “Once the agent has been internalized by the cells, the release of the diphtheria toxin essentially stops protein synthesis, and the cells die from within,” Dr. Konopleva said. The results of a multicenter pilot trial of SL-401, published in Blood last year, are promising. Of nine patients with recurrent or chemotherapy-refractory BPDCN who were evaluable for response, five had a complete response and two had a partial response after just one cycle of SL-401. The median response duration was 5 months (range, 1–20+ months).
“It was an active drug to say the least,” Dr. Pemmaraju said. “Some of these patients’ debilitating skin lesions disappeared, the bone marrow disease improved, and the lymph nodes improved.”
“It’s clear that BPDCN is highly sensitive to this approach,” Dr. Konopleva agreed. “And we’re hoping that SL-401 could be used instead of or in conjunction with stem cell transplantation to improve patients’ survival outcomes.”
The study reported few grade 3 or 4 toxic effects—thrombocytopenia, transaminase elevations, neutropenia, and hyponatremia—all of which were transient. The hyponatremia and milder adverse effects experienced by some patients appeared to be related to vascular leak syndrome. The low-grade effects included hypoalbuminemia, edema, hypocalcemia, uremia/elevated creatinine, fatigue, and headache; although these usually resolved within a few days, persistent hypoalbuminemia was managed with parenteral albumin and diuretics.
“The differential expression of CD123 between tumor and normal cells is very important, because otherwise you’d see more toxic effects.” Dr. Konopleva said. “CD123 is expressed on a fraction of normal hematopoietic stem cells, causing some degree of suppression of normal bone marrow. Liver function abnormalities are common in patients who receive SL-401, but it’s not very clear why this is the case.
“So we still see some toxicity,” Dr. Konopleva continued, “but we believe that at least for the malignancies that express very high levels of the receptor, like BPDCN, there’s clearly a therapeutic window where SL-401 can affect the tumor without causing major side effects.”
Following the promising findings of the pilot study of SL-401 in BPDCN patients, clinical trials of the drug at MD Anderson and other centers are now enrolling patients with other hematological diseases. “Oftentimes in oncology, discoveries from rare diseases can spur research in other tumor types,” Dr. Pemmaraju said. “That’s what’s happened here.”
Drs. Pemmaraju and Konopleva, as part of an interdisciplinary team of collaborators, are now conducting a multicenter phase I/II trial of SL-401 that includes patients with AML as well as those with BPDCN. The investigators have just submitted the preliminary results of their trial to the American Society of Hematology and hope to present these findings at the society’s annual meeting in December.
While earlier studies of SL-401 have indicated potential activity against AML, Dr. Pemmaraju said, “The results of our ongoing trial will shed more light on this subject.”
“I think it remains to be seen what the benefit in AML will be,” said Dr. Konopleva, the trial’s principal investigator. “There’s a lot of hope that SL-401 will be successful, but I think we need more data to determine that.”
Myeloproliferative neoplasms and CMML
Dr. Pemmaraju, extending what he’s learned about BPDCN to other rare hematological diseases, is the principal investigator for another clinical trial of SL-401, this one for patients with high-risk myeloproliferative neoplasms. This group of chronic blood disorders includes the three classic myeloproliferative neoplasms: polycythemia vera (excess red blood cells), essential thrombocytosis (excess platelets), and myelofibrosis (abnormal bone marrow resulting in decreased red blood cell production). Other, rarer myeloproliferative neoplasms include hypereosinophilic syndromes (also called hypereosinoophic disorders) and systemic mastocytosis.
“Among the three classic myeloproliferative neoplasms, myelofibrosis is the most deadly; it can turn into an acute process very quickly,” Dr. Pemmaraju said. “We see patients with such varied outcomes with myelofibrosis—for example, a person with lower-risk disease may have decades to live, but a patient whose disease transforms or starts as high risk may have only a few years.”
Although myeloproliferative neoplasms are more common than BPDCN, they have very few U.S. Food and Drug Administration–approved therapies. In fact, myelofibrosis has only one, ruxolitinib, which is for intermediate-to high-risk disease. And the only standard therapies for CMML are those already approved for myelodysplastic syndrome. However, studies have shown that in some cases, myeloproliferative neoplasms and CMML express CD123.
“So we have these other life-threatening blood cancers that have little to no standard therapy,” Dr. Pemmaraju said. “Now that we’re seeing that CD123 can be targeted in BPDCN, we’re running a new clinical trial of SL-401 dedicated to this other set of relatively rare diseases.”
The multicenter four-arm trial is currently enrolling patients with myelofibrosis, CMML, systemic mastocytosis, and advanced symptomatic hypereosinoophic disorders.
Minimal residual disease
Researchers also want to see if SL-401 can prevent relapse in patients with high-risk disease that is in remission. Dr. Konopleva is the principal investigator for a phase I/II clinical trial of SL-401 in AML patients with minimal residual disease.
“It’s believed that this approach may be most effective in targeting the CD123-expressing stem cells that survive standard chemotherapy,” Dr. Konopleva said. “Patients with high-risk AML in remission may or may not have detectable residual disease, but based on their clinical experience, we know that their survival is very short and they relapse early on; and cytotoxic chemotherapy usually doesn’t help to cure them.”
By eliminating the stem cells of minimal residual disease, Dr. Konopleva said, she and her colleagues hope to prevent relapse. “We are hopeful that this approach will be very beneficial, because some of the other maintenance approaches with chemotherapy have not shown substantial benefit. We hope we can change that,” she said.
The recombinant fusion protein approach used in SL-401 for targeting CD123 is the furthest along, but other ways of targeting CD123 are in the works.
“We’re very interested in CD123 as a tumor-specific antigen, and of course there are other approaches that we can use to target it,” Dr. Konopleva said.
Such approaches include the use of monoclonal antibodies conjugated with cytotoxic agents, which have been shown in preclinical trials to target and destroy CD123-expressing cells; “naked” antibodies against CD123, which have shown promise in AML patients with minimal residual disease; T cells engineered to express CD123-specific chimeric antigen receptors; and bispecific T cell engager antibodies, which can be engineered to link T cells to CD123-expressing tumor cells.
“We’re going to learn as much as we can about CD123’s modulation behavior before, during, and after therapy. We’ll continue to explore all tumors, solid and hematological, to see which of these express CD123 and in what proportion,” Dr. Pemmaraju said. “Once we identify the tumors that could be targeted, we can develop clinical trials that are safe and efficacious for testing new treatments.”
For more information, contact Dr. Naveen Pemmaraju at 713-792-4956 or Dr. Marina Konopleva at 713-794-1628.
Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 2014;124:385–392.
OncoLog, October 2015, Volume 60, Issue 10