Daniel J. DeAngelo, MD, PhD, associate professor of Medicine, Harvard Medical School, physician, Adult Leukemia Program, Dana-Farber Cancer Institute, discusses rates of cytokine release syndrome (CRS) with obecabtagene autoleucel (obe-cel; formerly AUTO1) in acute lymphoblastic leukemia (ALL).

Obe-cel was previously evaluated in the phase 1 ALLCAR19 trial (NCT02935257) in patients with select B-cell malignancies. The agent will be further explored in patients with ALL in the phase 1/2 FELIX trial (NCT04404660).

Compared with known rates of CRS with other CAR T-cell therapies, patients who received obe-cel had lower instances of severe CRS, DeAngelo explains. Instances of grade 1 or 2 CRS were reported, though there were limited cases of grade 3 or 4, with no cases of grade 5, DeAngelo adds.

Other neurotoxic adverse effects (AEs) were also limited, DeAngelo says. The lower affinity CD-19 binder of obe-cel resulted in less severe T-cell activation, leading to lower rates of severe CRS and neurotoxicity, DeAngelo concludes.

Videos

Daniel J. DeAngelo, MD, PhD, discusses rates of cytokine release syndrome  with obecabtagene autoleucel in acute lymphoblastic leukemia.


Dr. DeAngelo on Rates of CRS with Obe-cel in ALL

Daniel J. DeAngelo, MD, PhD, associate professor of Medicine, Harvard Medical School, physician, Adult Leukemia Program, Dana-Farber Cancer Institute, discusses the exploration of uproleselan (GMI-1271) plus chemotherapy in relapsed/refractory acute myeloid leukemia.

A phase 3 study (NCT03616470) is evaluating the efficacy and safety of uproleselan plus chemotherapy, vs placebo plus chemotherapy. The primary end point of the study is overall survival.

Eligible patients for this trial could be in first or second relapse after failing on an anthracycline regimen, DeAngelo says. Additionally, the study will utilize 2 different chemotherapy backbones of mitoxantrone, etoposide, and cytarabine (MEC), or fludarabine, cytarabine and idarubicin, DeAngelo explains. Notably, the MEC backbone was studied with uproleselan in a phase 1/2 trial (NCT02306291). Granulocyte colony stimulating factor (G-CSF) will not be used in the trial since safety concerns of G-CSF and E-selectin have not been thoroughly studied, DeAngelo notes.

Despite challenges of the COVID-19 pandemic, the phase 3 trial has met its accrual, DeAngelo continues. Investigators are waiting for the appropriate number of events before the study is unblinded, DeAngelo concludes.

Daniel J. DeAngelo, MD, PhD, discusses the exploration of uproleselan plus chemotherapy in relapsed/refractory acute myeloid leukemia.


Dr. DeAngelo on the Exploration of Uproleselan Plus Chemotherapy in R/R AML

I want everybody to have an opportunity to comment on this really nice review of 6 highlighted cases to try to review the breadth of the world of systemic mastocytosis. Dr Bose, let’s start with you.

 If I may continue a little bit the same thread that you and Dr Wang were discussing just now. I think you both made great points. Maybe there are these cases where 

 is driving the condition, and they would respond to avapritinib. But today, the way to get avapritinib would be to find those mast cells. I think that’s an excellent point that ties what both of you were saying.

Dr Lugar, any thoughts on the complex management from a different perspective than an oncologist?

 These are great cases, and I really feel that having that multidisciplinary approach, having partners in care, not only helps us identify patients but also helps us to think about their best care and their best cases. Having pathology looking for and thinking carefully about how to process the specimen so they can have a higher diagnostic yield. Having good partners in GI [gastroenterology] oncology certainly helps the allergist. I feel like these types of discussions are great to educate all of the health care providers who might be seeing it, and who may not even be aware, and to seek out your team approach so that we can do best by these patients.

I work in a luxury of riches. We have allergy/immunology, which I am sure you know, in our group. We have identified a gastroenterologist who seems to have taken ownership. We have 2 pathologists who have taken ownership, a molecular group, and then I wear the hat as the hematologist. Thus, it’s all of us together and sometimes it’s “tag you’re it,” depending upon what is the problem. If the patient needs cytoreductive therapy, it’s me, but more often than not I am having trouble with the GI or the allergy component, and it’s nice to be able to pass the baton to a colleague. Dr Wang, any last thoughts on the histopathology?

 I think the people in general practice should raise suspicion, that’s the most important thing. I think even though you are not 100% sure the patient may have mast cell, just say, “Rule out mast cell, or rule out this.” At least give us something that you are looking for, then we can initiate the proper work-up.

Thank you. With that, I want to thank my esteemed colleagues, Dr Bose and Dr Wang from MD Anderson [Cancer Center], Dr Lugar from [Duke Health in] North Carolina, and myself from Dana-Farber [Cancer Institute]. I want to thank you for participating in this enriching and informative discussion. I want to thank our audience as well. I hope that you found this 

 panel discussion to be engaging, and hopefully it’s helpful for your understanding for optimal care of patients with systemic mastocytosis. Thank you very much.

The panel of experts in SM highlight the unmet needs in the clinical care of systemic mastocytosis.

Unmet Needs in SM Treatment

Thank you very much. That was a great case. It reminds me of some of my cases. I think this would have been missed if you had a smaller biopsy and you might have missed that little bit of mast cell cluster. It’s important to look because I have picked up a couple of cases like this. I think it’s really driven back by the high 

 mutation occur in the hierarchy of all these other mutations? Also, if the 

 mutation is a very slow allele frequency and not representative of entire disease, then targeting that small percentage is not going to do it. But in this case, the variant allele frequency [VAF] for the 

 mutation was 41%, arguing that the clone size was greater than 80%, so the disease is probably being driven by 

. The rest of the questions in my opinion are rather moot because SM-AHN [systemic mastocytosis with an associated hematologic neoplasm] is the disease, and then your particular example is a 

-driven disease. Are the C findings driven from the mast portion or the CMML [chronic myelomonocytic leukemia] portion? They are all driven by 

. Also, I would argue that this is a patient, and we have seen patients, and I have had patients, who actually respond well to KIT inhibition, either midostaurin or avapritinib. Dr Bose?

 Actually, this is a very interesting and important topic where I think every case is a little bit different. Now, what we traditionally are taught to do is to clinically assess whether the C finding is attributable to the mast cell component or to the AHN. But you bring up a very good point Dan that if the 

 VAF [variant allele frequency] is very high, then it’s a bit moot because if you can hit that target you’re going to help all the lineages that the mutation is in. The NCCN [National Comprehensive Cancer Network] guidelines also say that the clinician should first determine what is more urgent to treat and what the organ damage is stemming from. But as was shown in the avapritinib presentation at EHA [European Hematology Association annual meeting] this year, even other lineages, such as eosinophils and monocytes, can go down with avapritinib. Thus, again if 

 is the driver and it is present in more than 1 lineage, then hitting that might suffice. We don’t know that and certainly not in all cases, and I think combination therapies will be necessary, but there is some potential for a 

 This was a case before avapritinib. The patient actually was treated with hypomethylating agents [HMAs], followed by allogeneic stem cell transplant, and the patient had been in remission for 3 years.

My case was very similar, but my patient was a little bit older, not a transplant candidate, and didn’t respond to HMA therapy and then was coming in for a second referral. Actually, interestingly, she had these lesions on her skin that made me think that this patient may have SM [systemic mastocytosis]. She had classic uticaria pigmentosa. We got a tryptase level that was elevated, then went back and looked at her marrow, and sure enough she had SM-AHN. Although she didn’t respond to HMA, she responded beautifully to avapritinib, as you pointed out, and the whole clone changed. Her splenomegaly resolved, the monocytosis resolved. Thus, I think as Dr Bose has pointed out, these are difficult cases. These are complex cases, and you’re dealing with 2 different manifestations, at least pathologically. Sometimes they are somewhat distinct, but in this particular case they are really being driven by the 

 process, and this gives you another tool in the toolbox in order to treat these complex diseases.

The question is probably do you treat all as 

-mutated myeloid neoplasm instead? We have also seen cases, with few patients, but no mast cell aggregates at all. Those cases I think will probably respond as well.

As I mentioned at the beginning when I prefaced this, one of our pathologists went back and looked at all the patients who had a next-generation sequencing panel, and for those who were 

 D816V who did not have AML [acute myeloid leukemia], because you can see it in core binding factor, when we went back and looked retrospectively at the pathology, even if the pathologist had not found or did not initially detect mastocytosis, mastocytosis was seen. Thus, we had missed about 20%. These were a small subset of patients, but we had missed about 20% of cases. This is an illustrative case where there was a small mast cell component that may have been missed if you weren’t thinking, and then we went back and looked at it. We published this in the 

 last year. Also, just to highlight the point—mutations matter and 

 D816V, if it’s not a core binding factor disease, you have to think mast cells.

My point is if the patient has just CMML with a 

 mutation, you look for the mast cell aggregate, you cannot find it, but this patient still probably will respond to the treatment.

You’re right. I understand what your point is, but a lot of it is based on the tissue. If you get a bigger sample or better sample, I think mast cells are there. We were always able to go back and find it when we looked. There may be that conundrum in a patient or a sample that you’re just not able to identify it because of the tissue, but we were always able to go back and identify the mast cell component. The point is that you’ve got to think about it, and it does open the door for 

The panel of experts discuss the diagnosis and assessment of chronic myelomonocytic cell leukemia.

Chronic Myelomonocytic Cell Leukemia: Clinical Considerations

 is a rare disease that often first presents on the skin. It is characterized by the overaccumulation of mast cells (MCs), which can then penetrate such internal organs as bone marrow (BM).¹ Challenges in identification and diagnosis suggest that SM is underdiagnosed despite its low prevalence. Prognosis for cutaneous and indolent cases of SM is excellent, but it can be variable for patients with advanced cases.¹ Symptoms often vary depending on the location of the MC proliferation, rendering diagnosis and treatment difficult.

® video series, an expert multidisciplinary panel reviewed 6 clinical cases to illustrate both the complexity of SM and the best diagnosis and treatment practices for affected patients. This article presents highlights from the panelists’ discussion, with an emphasis on the epidemiology, diagnosis, and treatment of advanced SM.

At the outset of the conversation, panel host Daniel J. DeAngelo, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, highlighted the complexity of SM stating, “[SM] is a challenging condition with multiple classifications and presentations.” Part of this convolution stems from the variety of MCs themselves, which exist in most tissues and play a role in immunity and immune-related inflammation.

 Mast cell progenitors (MCPs) come from the BM, migrate through the blood, and usually mature in vascularized tissue.

 There, influenced by blood vessels, nerve endings, and the local environment, MCPs take on phenotypes from their specific tissues.

 In these tissues, stem cell factor (KIT ligand) provokes MCPs to develop into mature MCs.

DeAngelo, whose clinical practice is focused on the treatment of patients with acute and chronic leukemias as well as myeloproliferative disorders, added that this variety presents a fundamental challenge for all MC disorders, including SM. “[MCs] can be hard to elucidate [microscopically],” he said. Panelist Sa Wang, MD, a professor in the Department of Hematopathology, Division of Pathology/Lab Medicine, and section chief of the Department of Hospital Flow Cytometry Laboratory at The University of Texas MD Anderson Cancer Center in Houston, concurred, saying, “[MCs] can be very subtle.” She added: “especially in the [gastrointestinal (GI)] tract,…[MCs] can mimic a lot of things...like plasma cells. When plasma cells [lose] the cytoplasm, they can look like MCs, too.”

The panelists underscored that the diversity of MCs leads to a wide range of MC activation triggers, a variety of MC functions, and heterogeneous MC disorders, and a host of MC disorder symptoms. Allergens, drugs, venoms, and physical stimuli can activate MCs, which then can secrete a variety of mediators that can directly or ultimately affect blood vessel diameter, inflammation, T-cell activation, autocrine and paracrine activity, and other processes.

 MCs appear to play a role in a large number of physiologic and pathologic mechanisms.

The panelists acknowledged that MC disorders may result from pathologic increase in clonal MCs or pathologic activation of MCs.

 Nevertheless, a patient can receive a diagnosis of both mastocytosis—in which MCs expand and accumulate in the skin, bone marrow, and visceral organs—and MC activation syndrome (MCAS), a condition in which MCs are activated in a severe, recurrent, acute, and systemic manner.

 DeAngelo noted the complexity of this overlap, stating: “I find this to be the most challenging. Patients will have…MC activation syndrome, some with a clonal MC process, some without.”

Panelist Patricia L. Lugar, MD, MS, an associate professor in the departments of medicine and pediatrics at the Duke University School of Medicine in Durham, North Carolina, agreed, adding that mastocytosis and MCAS have similar clinical presentations. “We don’t have…fantastic clinical markers or biomarkers to…guide us for MC activation as opposed to a true clonal MC disorder,” she said. The diagnosis is further complicated because these 2 diseases and their symptoms “mimic so many others that are cardiovascular or have origins in other organ systems,” she noted. “Pulmonary [problems], postural orthostatic tachycardia syndrome, multiple food sensitivities, and food [allergies]” all cause symptoms that overlap with mastocytosis and MCAS, and they must be ruled out in a diagnosis, Lugar emphasized. “By symptomatology alone, it’s very confusing to really figure out what the patient is experiencing.”

Classification of SM can also be a challenge. To account for the heterogeneity of the disorders that fall under the mastocytosis classification

 and in keeping with findings of other clinicians and investigators,

 the panelists cited the World Health Organization’s (WHO’s) 2016 criteria for the classification of myeloid neoplasms

 as foundational to understanding and classifying SM. These criteria set SM apart from localized MC tumors and varieties of cutaneous mastocytosis, which are not systemic.

The distinguishing feature of SM is the penetration of MCs into internal organs—including the BM—at multiple locations within the organ or organs.

 As DeAngelo explained, to diagnose SM according to the WHO, “you have to have 1 major and 1 minor or 3 minor criteria.” The major criterion is multifocal clusters of at least 15 MCs per cluster in 1 or more visceral organs. Clinicians usually see this clustering in the BM. Of the 4 minor criteria, the first is that at least one quarter of MCs in the BM are atypical or spindle-shaped if they are in the visceral organs. The second is a KIT point mutation at codon 816 in infiltrated organs. The third is exhibition of CD2 and/or CD25 in an infected (but extracutaneous) organ or in the blood. The fourth—which is not a valid criterion if an unrelated myeloid neoplasm exists—is a baseline serum tryptase level above 20 ng/ mL.

 DeAngelo presented his first case as a clear example of SM, stating, “This person had these huge, dense infiltrates …, a KIT mutation…, a CD25…aberrantly expressed…, [and] tryptase [level]…in the 100s [ng/ mL]…so he clearly met 1 major and 3 minor [criteria]. Any way you slice or dice it, this patient met the diagnosis of [SM].”

Panelist Prithviraj Bose, MD, associate professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, concurred with DeAngelo’s diagnosis. “Absolutely,” he said. “This is a very clear-cut case of SM, meeting multiple criteria.”

Bose also called attention to WHO’s subclassifications of SM into indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic (non-MC lineage) neoplasm (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL).

 Adding that DeAngelo’s first case had “a lot of C findings [that indicate organ damage from MC infiltration], as well,” Bose highlighted that the WHO defines most of these SM classifications according to the presence or absence of B findings (that indicate high MC burden across multiple organs or the blood but without organ damage) and C findings. ISM and SSM have no C findings; SSM has 2 or more B findings. ASM and MCL have C findings; MCL has MCs of 20% or more on BM smears.

 ASM and MCL are classified as advanced SM (AdvSM); SM-AHN is sometimes considered an AdvSM and otherwise considered as additional to 1 of the other 4 classifications.

Bose underscored that, once the presence or absence of C findings has been determined, WHO guides clinicians to determine whether an associated hematologic (non-MC) lineage neoplasm (AHN) is present and SM-AHN can be diagnosed. “Traditionally,” Bose added, “we are taught to…clinically assess whether the C finding is attributable to the mast cell component or to the AHN.” This is in an effort to treat the diseases separately and requires both the application of other disease-related markers and the classification of the AHN according to separate WHO criteria.

However, Bose highlighted that WHO’s SM-AHN model has been challenged. A mutation-adjusted risk score (MARS) for AdvSM that was proposed in 2019 may improve up-front treatment stratification for these disease states by guiding clinicians to diagnose according to 5 risk factors associated with overall survival (OS): age older than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 109 /L), presence of 1 high-molecular-risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1), and presence of 2 or more high-molecular-risk gene mutations.

 As AdvSM has a poor prognosis, as SM-AHN accounts for 70% to 80% of all patients with AdvSM (if considered an AdvSM), and as SM-AHN is the most heterogenous SM subtype, diagnosing according to MARS may improve AdvSM outcomes.

 Bose added that therapeutic advances have also made distinguishing between SM and a concurrent AHN less important. KIT D816V is the most important somatic mutation in SM-AHN and, in a large majority of patients, exists in both the SM and the AHN.

 “If the KIT [variant allele frequency (VAF)] is very high,” and “if you can hit that [KIT D816V] target,” the distinction between SM and AHN “is a bit moot.” He added, “Even other [AHN] lineages such as eosinophils and monocytes can go down with avapritinib,” which is a selective KIT D816V inhibitor.

SYMPTOMS, REFERRAL, AND DIAGNOSTIC PATTERNS

The specialists noted that most of their patients with SM come by way of referral. Lugar, an expert in allergy and immunology, underscored that anaphylaxis frequently is a presenting symptom. “We [often] see patients with recurrent anaphylaxis. As part of the workup, if the story fits with other symptoms, we will usually screen for muscle disorders,” she noted. The next most common symptom is reaction to venom stings (eg, from flying insects). “Individuals [who] have had either profound allergic symptoms during the sting [eg, anaphylaxis or cardiovascular symptoms, syncope, difficulty in resuscitating, need for multiple doses of epinephrine, evidence of a possible previous anaphylactic episode] will be screened,” Lugar explained.

DeAngelo observed that he gets referrals from allergy and immunology experts for patients with recurrent anaphylaxis or reactions to flying insect stings who have met the criteria that Lugar outlined. However, working in a general hospital, he also gets referrals from dermatologists, gastroenterologists, and fellow hematologists. “Dermatology will [see] a rash, [suspect] urticaria pigmentosa or the telangiectasia [macularis] eruptiva perstans, make a biopsy, and refer a patient. Additionally,” he noted, “patients with irritable bowel syndrome come to an urgent evaluation, and a gastroenterologist [will] refer [them to me].”

Referrals are also common from hematologists, added Bose. “Usually, they’ve been picked up by a dermatologist who’s biopsied the rash and sent them to a community hematologist, who then refers the patient to us.”

According to Lugar, the screening includes a physical examination. In this, the clinician is looking for telltale clinical symptoms (eg, urticaria pigmentosa, telangiectasia macularis eruptiva perstans). “We do a skin exam, take clinical history, and then screen for serum tryptase [levels]. We don’t usually do urine histamine or prostaglandin [levels] at that point in time,” said Lugar. “Screening… may also be warranted,” she continued, “… even if the tryptase [level] is not excessively over the reference range, if a patient has symptoms that have been persistent, such as flushing, or if we do see signs of possible lesions consistent with cutaneous mastocytosis.” At that point, she noted, clinicians may consider c-KIT, looking for mutations D816V and c-KIT by peripheral blood testing. “If we see signs and symptoms that it’s very likely the person has a [MC] disorder, and based on the level of tryptase, [I] would we go ahead and actually recommend a [BM] biopsy,” Lugar said.

Given the noted difficulties of understanding and identifying the mechanisms of SM, diagnosis is often made differentially, Lugar added, which itself is associated with several challenges. “[W]e don’t have … fantastic clinical markers or biomarkers to also guide us for [MC] activation [compared with those for] a true clonal [MC] disorder,” Lugar said. “We’ve had a number of people with monoclonal [MC] disorders where the aggregates on biopsy might be quite small but [the patients] have a mutation at c-KIT.”

Lugar observed that she examines what brings on the symptoms and what has worked before measuring the serum tryptase level for a baseline. “[If patients] feel that they’ve had anaphylaxis or symptoms that are characteristic, potentially of an allergic reaction, I’ll try to get them to get a tryptase [level] at that time so we can prove that it’s [MCs] [that are] bringing about this complex set of symptoms,” said Lugar. She further explained that genetic analyses may be important even if the clinician does not suspect a diagnosable MC disorder, because understanding the mutation can help.

Genetic testing, such as next-generation sequencing, which DeAngelo referred to as a “rapid heme panel,” can identify specific mutations (eg, in KIT, SRSF2, TET2, and COX1) that may respond better to certain therapy. If a targetable mutation is not identified, Lugar observed, clinicians likely need to experiment with a treatment plan that ameliorates some of the symptoms. “It is [often] a long-term [process], where you start with your assessment, and you continue to assess and use whatever tools available to try to work toward a diagnosis,” she noted.

Given these challenges, the panelists underscored that the information from referring physicians is critical for an accurate diagnosis. However, they noted that this path can be complicated. Sometimes, noted DeAngelo, “the referring physician [does] not…specif[y] to the pathologist [her suspicion of mastocytosis],” and the hematologist can miss it. Moreover, according to Wang, hematologists often “cannot afford to do an [MC] workup for every GI biopsy. They have to have some suspicions,” and these must come from the pathologist or referring physician. Additionally, Bose reiterated that if “SM is not on the radar, then absolutely, it could be missed.”

CURRENT AND EMERGING TREATMENT OPTIONS FOR ADVANCED SM

Treatment options for advanced SM are limited, which likely reflects the diagnostic challenges and lack of clinical biomarkers. Historically, clinicians have relied on chemotherapy and stem cell transplants to treat aggressive SM, but targeted options are available, and others are in development.

Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT. It is FDA approved for the treatment of patients with advanced SM. In a 10-year follow-up study from a phase 2 trial evaluating patients with organ damage who received 100 mg of midostaurin given twice daily, the overall response rate (ORR) was 69%, and median OS was 40 months. Additionally, 2 of 26 patients achieved complete remission (CR) with ongoing therapy. The BM MC burden was reduced by greater than 50% in 68% of patients, and serum tryptase levels were reduced by more than 50% in 46% of patients.

When treating patients with midostaurin, DeAngelo noted, patients may experience nausea. For one of his cases, DeAngelo said, “I tried maximizing his antiemetics, [and] I had to reduce the dose to 50 mg twice daily.” Over the course of several months, the patient was able to tolerate the reduced dose and antiemetic regimen, which allowed DeAngelo to increase the dose back to 100 mg given twice daily. “My experience has suggested that patients have a dose-response curve, so I try to get as much drug as I can,” he explained. After over 1 year of therapy, the patient still had an elevated serum tryptase level, but it was under 20 ng/ mL, which is part of the criteria for remission.

For patients with aggressive SM who do not have the D816V c-KIT mutation or whose mutational status is unknown, imatinib is an FDA-approved treatment option. Wang described one of her cases, noting that imatinib may be effective for patients with well-differentiated SM with mastocytoma, a rare, often misdiagnosed type of an already rare condition. “[The patient] actually responded beautifully to [imatinib], and all the symptoms resolved—skin lesions, systemic symptoms. However, actually, she was [nonadherent], and [it] came back and recurred again. It was SM,” said Wang.

Wang also emphasized the importance of not classifying these patients as having MC hyperplasia because their disease may be associated with numerous other conditions (eg, lymphoplasmacytic lymphoma [which is also associated with a proliferation of MCs], chronic MC leukemia).

In June 2020, the FDA approved avapritinib for the treatment of adult patients with advanced SM, including those with aggressive SM, SM with an associated hematologic neoplasm, and MC leukemia. Avapritinib is a potent and selective KIT D816V inhibitor. In the phase 1 EXPLORER trial (NCT02561988), patients receiving avapritinib achieved a 75% ORR per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria.

 Responses were rapid with complete remissions over time. Investigators also observed improvements in MC burden, organ damage, patient symptoms, and quality of life.

Results from the phase 2 registrational PATHFINDER trial (NCT03580655) that were recently presented at the American Association for Cancer Research Annual Meeting 2021 showed the potential benefit of avapritinib in patients with advanced SM.

 In all, 52 patients with a diagnosis of advanced SM with at least 1 evaluable C finding received a starting dose of 200 mg of avapritinib given once daily. Patients with platelet counts less than 50 x 109 /L were excluded from the study.

The primary end point in the evaluable cohort was adjudicated ORR by modified IWG-MRT-ECNM criteria on mastocytosis. A prespecified interim analysis was planned after 32 patients had sufficient follow-up. Notably, 53% of patients in the interim analysis efficacy population received midostaurin previously, and 13% of patients in this population were treated with cladribine.

Interim analysis demonstrated an ORR of 75%, with 19% of patients achieving CR with partial hematologic recovery. In all, 31% of patients achieved partial remission, and 25% of patients experienced clinical improvement.

 “Clinical improvement means that their C finding improved or resolved, which, for most patients, is why they’re referring to [hematologists],” DeAngelo explained. Looking beyond the broader study population, DeAngelo noted that the findings held up across histological subtype and prior treatments. “The interesting thing about this study is that responses were seen regardless of the histologic subtype,” he said. “Responses were relatively equivalent regardless of whether patients were previously exposed to midostaurin, like the case I showed you, or whether they were midostaurin naive, [or] whether this was an initial treatment.”

With a median follow-up of 10.4 months, all responses are still ongoing. Median time to response was 2 months, and responses were maintained after dose reduction. Median time to CRs with partial hematologic recovery was 5.6 months. Patients’ responses also improved with time.

Avapritinib therapy led to a notable reduction in BM MCs, with 88% of patients achieving a greater than 50% reduction and 60% of patients achieving elimination of marrow MC aggregates. Additionally, 93% of patients achieved a greater than 50% reduction in serum tryptase level, 60% of patients achieved a 50% or greater reduction in variant allele frequency, and 66% of patients achieved a greater than 35% reduction in spleen volume.

Regarding adverse events (AEs), 5% of patients discontinued the regimen because of treatment, and 68% had a dose reduction because of an AE, most commonly; cytopenias.

Finally, patients receiving avapritinib experienced a significant reduction in total symptom score, with a mean change from baseline of 9.8 (P < .001) and a reduction in individual symptom scores.

 According to DeAngelo, these findings may have particular meaning for patients. “One of the important features of our job is to make patients feel better. And so here, you can see this significant rapid reduction in their total symptom score. All of these symptoms improved in patients who had them, so I think that that is just an important observation.”

Lugar agreed and expressed hope that these results would bear out in continued evaluation of avapritinib. “I hope that the same symptom score for indolent [cases] as well carries over in further trials, because that’s the most difficult thing—managing the chronic symptoms,” she said. “Even if we know these patients are stable, they don’t have a disease that’s going to be progressive, the majority of them, but managing the day-to-day symptoms is such a [benefit toward managing] the burden of disease.”

Bose noted that the PATHFINDER findings coupled with the EXPLORER data are particularly exciting because of not only the ORR, but also the rate of CRs. “This is a drug [that] is hitting the target to a greater depth,” said Bose. “This is a more potent and more selective inhibitor of mutant KIT, so I hope we are sparing wild-type KIT a little bit more. Not entirely, because we see myelosuppression, but hopefully more than we do with midostaurin,” he said.

As testing methods and treatment options expand, the rarity and complexity of SM will continue to present significant challenges regarding identification and management. “This is not an easy landscape to toil,” noted DeAngelo. Given the importance of making a definitive diagnosis, both from a molecular and a histopathologic perspective, DeAngelo believes that clinicians and pathologists must work together to ensure diagnostic accuracy. “You really [have] to help the pathologist out,” he said. “That’s where the interaction is so important, to really talk to the pathologist or your referring physicians.” Improved communication among specialists, coupled with emerging treatments that could potentially be used in broader populations, may better enable clinicians to optimize outcomes for patients as the field continues to evolve.

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Gotlib J, Radia DH, George TI, et al. Pure pathologic response is associated with improved overall survival in patients with advanced systemic mastocytosis receiving avapritinib in the phase I EXPLORER study. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual format. abstract 345. 

https://ash.confex.com/ash/2020/webprogram/Paper137413.html

DeAngelo DJ, Reiter A, Radia D, et al. Abstract CT023: PATHFINDER: interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM). 

81(13 supp):C2023. doi:10.1158/1538-7445.AM2021-CT023

3-month history of fatigue, abdominal distention, and lower-extremity edema

Rapid heme panel (RHP): KIT D816V mutation

Flow cytometry: MCs expressing aberrant CD25

Tryptase blood test (tryptase): 187 ng/mL

Platelet: 64 × 109 /L (thrombocytopenia)

Flow cytometry: MCs expressing CD117 and aberrant CD2

Blood differential test: 1 nucleated red blood cell (NRBC) (per 100 WBC)

CT scan: pathologic lymphadenopathy, small pleural effusion, ascites, and splenomegaly

Difficulty with nausea; maximized antiemetics

Able to slowly reescalate over 3 months back to 100 mg twice daily

Ascites resolved. Hepato-splenomegaly resolved.

BM shows partial remission from SM and tryptase level 19 (ng/mL, < 11.5)

“[An important] point [from this case is that] the [next-generation sequencing (NGS)] miss[ed] the mutation….[W]e, too, had a number of cases [of missing these important mutations] before we started doing the digital droplet PCR [polymerase chain reaction], where we were finding them to be KIT wild-type….We’ve [now started to] reflexively order the digital droplet PCR or the molecular diagnostics…if [we] find the NGS is negative.”

Chronic diarrhea,* weight loss,* and abdominal distension

Articles

Learn more about the epidemiology, diagnosis, and treatment of advanced systemic mastocytosis in this summary from an expert multidisciplinary case-based discussion.

Advanced Systemic Mastocytosis: Expert Insight into Epidemiology, Diagnosis, and Treatment

Daniel J. DeAngelo, MD, PhD, institute physician, chief, Division of Leukemia, Dana-Farber Cancer Institute, professor of medicine, Harvard Medical School, discusses the utility of moxetumomab pasudotox-tdfk (Lumoxiti) in hairy cell leukemia (HCL).

In September 2018, the FDA approved moxetumomab pasudotox, a CD22-directed cytotoxin, for the treatment of adult patients with relapsed/refractory HCL who received at least 2 prior systemic therapies, including a purine nucleoside analog. Since the regulatory decision, moxetumomab pasudotox has been a utilized as a salvage therapy for patients with HCL. Moreover, the agent has demonstrated significant benefit for patients who have multiple relapses or short remissions, or do not respond to cladribine or pentostatin. In addition, this therapy can be administered in the outpatient setting, which has been beneficial during the coronavirus disease 2019 pandemic, DeAngelo explains.

As such, in clinical practice, moxetumomab pasudotox is typically reserved for patients who are refractory to nucleoside analogs, defined as having a remission duration of less than 12 months, as well as those who have relapsed disease and are not candidates for aggressive nucleoside analog therapy, DeAngelo concludes.

Daniel J. DeAngelo, MD, PhD, discusses the utility of moxetumomab pasudotox-tdfk in hairy cell leukemia. 


Dr. DeAngelo on the Utility of Moxetumomab Pasudotox in HCL 

Daniel J. DeAngelo, MD, PhD, institute physician, chief, Division of Leukemia, Dana-Farber Cancer Institute, professor of medicine, Harvard Medical School, discusses the mechanism of action of pevonedistat in myelodysplastic syndrome (MDS).

Pevonedistat is a NEDD-8 inhibitor that targets proteins for the proteasome, says DeAngelo. Moreover, the agent has demonstrated utility in combination with chemotherapeutic agents, such as hypomethylating agents (HMAs), DeAngelo explains. HMAs, such as azacitidine and decitabine, are standard options for patients with high-risk MDS because of established response rates; however, these response rates remain low. 

Notably, adding pevonedistat to HMAs does not appear to increase toxicity, DeAngelo says. Moreover, data have shown that combining the agent with HMAs can improve response rates for patients with high-risk MDS. However, confirmatory phase 3 trials are needed to parse out the benefit the combination may yield for patients, concludes DeAngelo. 

Daniel J. DeAngelo, MD, PhD, discusses the mechanism of action of pevonedistat in myelodysplastic syndrome. 


Dr. DeAngelo on the Mechanism of Action of Pevonedistat in MDS 

Daniel J. DeAngelo, MD, PhD, institute physician, chief, Division of Leukemia, Dana-Farber Cancer Institute, professor of medicine, Harvard Medical School, discusses the utility of the investigational agent pevonedistat in myelodysplastic syndrome (MDS).

Pevonedistat is a novel inhibitor of the NEDD8-activating enzyme that has been under evaluation for some time, says DeAngelo.

The agent may offer an alternative treatment to proteasome inhibitors with a similar dosing schedule, explains DeAngelo.

Notably, pevonedistat given as monotherapy is associated with limited toxicity, which lends itself to combination therapies, DeAngelo says. The toxicities that are associated with the agent are similar to those observed with hypomethylating agents (HMAs). 

Additionally, the agent appears to augment the activity of HMAs without increasing toxicity, concludes DeAngelo.

Daniel J. DeAngelo, MD, PhD, discusses the utility of the investigational agent pevonedistat in myelodysplastic syndrome.



Dr. DeAngelo on the Utility of Pevonedistat in MDS

Daniel J. DeAngelo, MD, PhD, medical oncologist, Dana-Farber Cancer Institute, discusses ongoing trials of patients with acute myeloid leukemia (AML).

Investigators are researching targeted approaches for patients with relapsed/refractory AML. For patients with 

 mutations, physicians are focusing on a combination therapy. Using venetoclax (Venclexta) to target BCL-2 is an additional study that is being researched, says DeAngelo.

There is a variety of phase I studies looking at CD33-directed therapy, CD123-directed therapy, and chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy has seen success in other hematologic malignancies, with 2 FDA approvals of tisagenlecleucel (Kymriah) in acute lymphocytic leukemia and axicabtagene ciloleucel (Yescarta) in patients with relapsed or refractory non-Hodgkin lymphoma.

Dr. DeAngelo Discusses Ongoing Trials in AML

Daniel J. DeAngelo, MD, PhD, director of clinical and translational research, Adult Leukemia Institute (ALL), Dana-Farber Cancer Institute, discusses inotuzumab ozogamicin compared to standard chemotherapy in the INO-VATE study for patients with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin is an anti—CD22 antibody-drug conjugate. Over 90% of patients with B-cell ALL express CD-22 on their surface. Several phase I and II studies showed that inotuzumab ozogamicin had very high clinical activity/  

 In the phase III trial INO-VATE trial inotuzumab ozogamicin demonstrated a median PFS of 5.0 months (95% CI, 3.7-5.6) compared with 1.8 months (95% CI, 1.5-2.2) with standard chemotherapy (HR, 0.45; 97.5% CI, 0.34-0.61; 

The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 80.7% with inotuzumab ozogamicin (95% CI, 72.1-88.7) compared with 29.4% of those who received standard chemotherapy (95% CI, 21.0-38.8; 

Daniel J. DeAngelo, MD, PhD