Pemmaraju Discusses Development of Targeted Therapy for BPDCN

Naveen Pemmaraju, MD

Associate Professor, Department of Leukemia

Division of Cancer Medicine

The University of Texas

MD Anderson Cancer Center

Houston, TX

CASE SUMMARY

• A man aged 67 years was referred from a dermatologist.
  • Referred initially to dermatologist for progressive, persistent, cutaneous nodules that patient first noticed 3 weeks prior
• Fatigue, 5-kg weight loss over 3 months
• Medical history: sinusitis; no major comorbidities
• Physical exam: notable for multiple purpuric nodules (measuring ≤5 cm on arms, legs, torso). No palpable adenopathy, hepatosplenomegaly
• ECOG performance status: 1
• Laboratory results: white blood cells, 14.1 × 10³/μL; hemoglobin, 8.9 g/dL; platelets, 54 × 10³/μL. Differential blood count revealed 12% blasts, 32% neutrophils, 16% monocytes, 40% lymphocytes.
• Skin: purpuric nodule
• Peripheral blood smear: blastic cells with large and round or slightly irregular nuclei; blast cytoplasm stained grayish-blue without granules or Auer rods
• Bone marrow biopsy showed 40% blasts by morphology; 80% cellular marrow with interstitial infiltrate.
• Immunohistochemistry of neoplastic cells: CD123, CD4, CD56, TCL1 positive
• Flow cytometry: CD4, CD56, CD123; negative for CD34 and T- and B-cell lineage-specific markers
• Cytogenetics: 46,XY
• Lumbar puncture did not indicate central nervous system involvement.
• The patient was ultimately diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN) based on clinical and histopathologic findings.
• The patient received tagraxofusp-erzs (Elzonris) 12 μg/kg per package label for frontline therapy and achieved a complete response (CR) after 1 cycle of therapy.

Targeted Oncology: What was the background of your research in developing a targeted treatment for BPDCN?

PEMMARAJU: BPDCN treatment has been one of the great aspects of my career in the past 6 or 7 years. I’m enthusiastic to share it. [All these] patients who were coming to our clinic with BPDCN…were dying. We borrowed from AML [acute myelocytic leukemia] and ALL [acute lymphoblastic leukemia] therapies, which you regularly use a 7 + 3 regimen for AML, hyper-CVAD [cyclophosphamide (Cytoxan), vincristine (Oncovin), doxorubicin (Adriamycin), dexamethasone], CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or other lymphoma regimens. BPDCN is a very chemotherapy-sensitive, steroid-sensitive disease, so a lot of patients will go into quick remission. However, there was high toxicity and early mortality, something like 30% to 40%, and then serious rapid relapse rates and death within 1.0 to 1.5 years in the European series and ours.

The breakthrough in my career was the finding— by my friend and colleague Arthur E. Frankel, MD—that CD123, which was previously shown to be overexpressed in most leukemic stem cells, was 100% overexpressed in BPDCN. In his laboratory, he put together a modified diphtheria toxin in the recombinant human IL-3 and made an agent at the time called DTIL3.

He initially wanted to treat CD123-expressing tumors [including] MDS [myelodysplastic syndrome], AML, and BPDCN, which was not well known back then. He and I collaborated not only for the AML and MDS but also for BPDCN, and we published that experience as a pilot study in Blood 10 years ago.¹

We had 7 of 9 responders with BPDCN after just 1 cycle of therapy. That’s all we had back then, and no company was involved yet. The median age was 70 years, and all patients were male. It was a breakthrough. There was an editorial by David J. Fitzgerald, PhD, from the NIH [National Institutes of Health] heralding that this could be the start of a new field.²

We went on to do the first multicenter, multicycle study of tagraxofusp, and then the [manufacturer], Stemline Therapeutics, got involved. The rest is history. We were able to do the study, which was very successful, and tagraxofusp received FDA approval in December 2018 in the United States as the first and only approved drug for BPDCN.³ [It is still the only approved] drug that targets CD123.

Q:What considerations are important to know when using tagraxofusp?

We got it into the National Comprehensive Cancer Network [NCCN] guidelines. The NCCN [guidelines] for BPDCN are tucked away in the AML guidelines.⁴ For BPDCN treatment induction, tagraxofusp is one of the preferred regimens. The 12-μg/kg dose is what we studied. In the clinical trial, we started at a dose of 7 μg/kg, 9 μg/kg, and then 12 μg/kg.

Tagraxofusp carries a potentially fatal black box warning of capillary leak syndrome [CLS], so for the first cycle, we need to hospitalize and watch the fluid and albumin levels. The subsequent cycles can be given as outpatient. People can go into a CR very quickly after just 1 or 2 cycles. In addition to that, as we mentioned, we can use AML or ALL regimens. We prefer ALL-based regimens. That’s what our group and others have found to be more effective, and then in older, frail patients, we use CHOP or a lymphoma-based regimen.

I should also mention that allogeneic hematopoietic cell transplant appears to be very curative, particularly for young patients, so we do send all our patients to…my colleagues who do our BPDCN transplants.

Not everyone is going to be able to get the drug. It’s expensive, so you must get insurance and the hospital to support it. Albumin [level] should be 3.2 g/dL or higher in these patients, and they cannot have severe cardiopulmonary disease. There are some restrictions on this new diphtheria toxin modified drug.

For patients who don’t qualify, we still use other mechanisms. If [patients are] older and frail, I use an HMA [hypomethylating agent] and a venetoclax [Venclexta]-based approach, which you’re all familiar with from older AML, or an older ALL mini-CVD [cyclophosphamide, vincristine, dexamethasone]/venetoclax approach…. In [clinical trials in] the relapsed setting, we do have novel CD123-targeted agents like pivekimab sunirine [IMGN632], which can be done in the frontline or relapsed setting. Also, [there are trials of CD123-targeted] CAR [chimeric antigen receptor] T-cell therapy. I’ve moved away from using radiation therapy, which is simply a palliative measure. Systemic cytotoxic chemotherapy and venetoclax have activity in BPDCN.

What was the trial design for the study of tagraxofusp for BPDCN?

Tagraxofusp was just 1 of the great findings in a field where there were no breakthroughs. With Stemline Therapeutics, we conducted 4 trials in 1. Stage 1 was more of a traditional 3 + 3 design that we’re used to. We started out at 7 μg/kg, and then we got all the way up to 12 μg/kg. We took patients with both frontline and relapsed/refractory disease. There was no MTD [maximum tolerated dose] reached. We already started seeing remissions in activity, and the CLS, so by investigator [selection], we chose 12 μg/kg as the dose to move forward with.

At the stage 2 or expansion stage, we enrolled both patients with frontline and relapsed/refractory disease [who received] the 12 μg/kg IV [intravenous] 5-day dosing. [High] efficacy was seen. The regulatory agency asked us to do a focused frontline study, so that is the stage 3, or the pivotal, confirmatory study. Approximately 13 patients, all [in the frontline setting], were enrolled. We were able to work with the company for the stage 4, or continued access, study, and I published those results recently in the Journal of Clinical Oncology.⁵

The stage 4 study had 65 patients in the frontline setting with this rare disease over approximately 4 or 5 years. The agent was given inpatient, at least in the first cycle, with the option of subsequent cycles outpatient. Patients had to have an albumin [level] of 3.2 g/dL or higher because of CLS.

How did the patients respond in the original data analysis?

They did well. Of the first 29 patients in the front line who we treated with the 12-μg/kg dosing, 90%, almost all responded, and [72% had] CRs or a clinical CR [CRc], which indicates that you did a skin biopsy and there were unclear residual cells.

We gave tagraxofusp to one of my patients, a 71-year-old woman with [worse] performance status, and her lesions in the skin and bone marrow [resolved]. She went on to allogeneic hematopoietic cell transplant. We published these results in the New England Journal of Medicine (NEJM) in April 2019.⁶

After the approval in December 2018, the paper came out in the NEJM, which put us on the map, and this is what I’ve been dedicated to. We took a rare disease, and now we’ve got an NEJM paper, a first FDA approval for a CD123-targeted drug, and it includes pediatric approval in [patients] 2 years and older. It is a full approval, not an accelerated approval.

The other key aspect is the advocacy of the FDA, which I’ve had only a good relationship with. They want to advocate for patients with rare diseases, so we are starting to see approvals in pretty rare diseases. We got the drug approved in the United States, and it also got approved in Europe in January 2021, but it was restricted to adults in the frontline setting only.

BPDCN is finally making its way to [medical board exams]. I just had a fellow tell me that they took one of the practice exams for ASH [American Society of Hematology] or ASCO [American Society of Clinical Oncology], and there was a question on BPDCN, so it is going to start being in the training, and you are going to start hearing about it in practice. Obviously, once there’s a drug and an NEJM paper, suddenly pathologists and dermatologists will start diagnosing it and patients will start coming to the clinic.

Could you discuss the updated efficacy and safety outcomes with tagraxofusp?

One question I get asked when I speak about BPDCN is, “You have a drug approved for a rare disease that I’ll never see. But what’s the deal with it…and is it safe?” We published these extension data recently in the Journal of Clinical Oncology, and it was well received by the community. It [enrolled a total of 89] patients now vs the initial 29 patients, so we almost tripled the patients in the NEJM paper.

Overall, 84 patients were treated. I’m not focusing on the relapsed/refractory patients because they are sick and don’t do well regardless of what you give them. For the 65 patients [in the frontline setting], 80% were male, and the age range was 68 to 84 years. We [were able to treat] an 84-year-old patient. Most of the patients had skin involvement, approximately 92%, and half had bone marrow involvement.

The overall response rate [ORR] held up decently at 75% [Table⁵]. It was 90% in the original study. We bridged 32% of patients to a hematopoietic cell transplant. The median duration of CR plus CRc was 25 months, at a median duration of follow-up of 34 months. The rate of overall survival [OS] was 55% at 12 months, 50% at 18 months, and a respectable 40% at 24 months.⁵ Remember, this is a disease where patients had a historical life expectancy of 1.0 or 1.5 years with cytotoxic chemotherapy.

After the approval in December 2018, the paper came out in the NEJM, which put us on the map, and this is what I’ve been dedicated to. We took a rare disease, and now we’ve got an NEJM paper, a first FDA approval for a CD123-targeted drug, and it includes pediatric approval in [patients] 2 years and older. It is a full approval, not an accelerated approval.

The other key aspect is the advocacy of the FDA, which I’ve had only a good relationship with. They want to advocate for patients with rare diseases, so we are starting to see approvals in pretty rare diseases. We got the drug approved in the United States, and it also got approved in Europe in January 2021, but it was restricted to adults in the frontline setting only.

BPDCN is finally making its way to [medical board exams]. I just had a fellow tell me that they took one of the practice exams for ASH [American Society of Hematology] or ASCO [American Society of Clinical Oncology], and there was a question on BPDCN, so it is going to start being in the training, and you are going to start hearing about it in practice. Obviously, once there’s a drug and an NEJM paper, suddenly pathologists and dermatologists will start diagnosing it and patients will start coming to the clinic.

Could you discuss the updated efficacy and safety outcomes with tagraxofusp?

One question I get asked when I speak about BPDCN is, “You have a drug approved for a rare disease that I’ll never see. But what’s the deal with it…and is it safe?” We published these extension data recently in the Journal of Clinical Oncology, and it was well received by the community. It [enrolled a total of 89] patients now vs the initial 29 patients, so we almost tripled the patients in the NEJM paper.

Overall, 84 patients were treated. I’m not focusing on the relapsed/refractory patients because they are sick and don’t do well regardless of what you give them. For the 65 patients [in the frontline setting], 80% were male, and the age range was 68 to 84 years. We [were able to treat] an 84-year-old patient. Most of the patients had skin involvement, approximately 92%, and half had bone marrow involvement.

The overall response rate [ORR] held up decently at 75% [Table⁵]. It was 90% in the original study. We bridged 32% of patients to a hematopoietic cell transplant. The median duration of CR plus CRc was 25 months, at a median duration of follow-up of 34 months. The rate of overall survival [OS] was 55% at 12 months, 50% at 18 months, and a respectable 40% at 24 months.5 Remember, this is a disease where patients had a historical life expectancy of 1.0 or 1.5 years with cytotoxic chemotherapy.

What are some adverse effects of tagraxofusp? How is CLS managed?

The adverse effects [AEs] are very important. Any novel drug has novel toxicities. I already said it has a black box warning for CLS. Fortunately for our patients, we did not uncover any new safety signals. CLS occurs in about 20% of patients, but only [3 patients] in the studies [died] from it.

CLS can be mitigated by replacing albumin, giving diuretics regularly, and watching the daily weight. If the person gets 1.5-kg weight gain or more in 24 hours, you hold the drug, and then if you go to the ICU [intensive care unit], unfortunately, it can be salvaged. High-dose steroids can reverse CLS. Use vasopressors if you need. You can rechallenge easily, as it’s usually only a first-dose phenomenon.⁷

Approximately 50% of the patients will have LFT [liver function test] abnormalities, usually in alanine aminotransferase or aspartate aminotransferase, and 50% will have thrombocytopenia. Most of these are restricted to cycle 1 as a first-dose exposure phenomenon.

Across the clinical trials including trials in other CD123-expressing tumors like myelofibrosis, AML, and CMML [chronic myelomonocytic leukemia], CLS is high across the board. It’s higher than the 20% [in BPDCN]. In all the trials, it’s in almost half the patients, if you consider grades 1 and 2. There were 2 fatal events, and they can be prevented and mitigated now that we know about the albumin cardiopulmonary status. CLS is seen in other diseases with other drugs [using] other bacterial toxins. It’s an entity with hypoalbuminemia, edema with weight gain, and hypotension.

Management of CLS is an evolving phenomenon. One thing we learned on the job was that education is key. I spend a separate half hour with patients, caregivers, and family. I tell them we got the drug approved in December 2018…. We lost patients on the trial because of CLS, which [is why the drug] has a black box warning that you need to know about. As always, put it out in front and be transparent [with patients]. Look at the albumin. If they’re not at 3.2 g/dL, they can’t get the drug.

Once they’re on the drug, it can displace albumin down, and then it’s OK to replace albumin [related to treatment]. But to get on the drug, your own albumin, not artificial, should be over 3.2 g/dL. Then, during the treatment, do rigorous screening. [Whether on] holidays, nights, or weekends, you’ve got to have someone watching the albumin, eyes and nose, weight, replacing albumin, and giving furosemide [Lasix] as needed. Of course, if a patient is crashing and getting into CLS, treatment with high-dose corticosteroids is lifesaving. While you’re [giving] furosemide or albumin, they might need antibiotics and other things. This is a little different from patients with APL [acute promyelocytic leukemia], who can get into a capillary leak differentiation syndrome.

_REFERENCES

_{1. 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(3):385-392. doi:10.1182/ blood-2014-04-566737}

_{2. FitzGerald DJ. Targeted diphtheria toxin to treat BPDCN. Blood. 2014;124(3):310-312. doi:10.1182/ blood-2014-06-578633}

_{3. FDA approves first treatment for rare blood disease. News release. FDA. December 21, 2018. Accessed June 14, 2023. https://tinyurl.com/4nyas7j4}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 3.2023. Accessed June 14, 2023. https://tinyurl.com/2z7vn9kk}

_{5. Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/ JCO.22.00034}

_{6. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637. doi:10.1056/NEJMoa1815105}

_{7. Elzonris. Prescribing information. Stemline Therapeutics Inc. Updated December 2018. Accessed June 14, 2023. https://tinyurl.com/ycksy3wc}