Activity Transcript

Chapter 1: Systemic Mastocytosis: Disease Overview and Pathogenesis

My name is Juliana Schwaab. I'm a medical hematologist from Manheim University in Germany, and I'm going to introduce SM. SM is a rare myeloid neoplasm characterized by a clonal accumulation and proliferation of mast cells in different organ systems, such as the skin, the bone marrow, the GI tract, lymph nodes, spleen, and so on.

In more than 95% of the patients, the disease initiating KIT D816V mutation can be detected using highly sensitive quantitative PCR assays. Usually, serum tryptase is elevated above normal limits, which would be less than 20 micrograms per liter. SM is a very rare disease. However, in terms of treatment and prognosis, the differentiation between mastocytosis and other disorders is of utmost relevance.

Indolent SM is usually accompanied by a normal lifespan. Whereas, in advanced phase disease, the life expectancy is significantly decreased. Symptoms in SM are manifold and usually reflect the organs involved. With regards to the skin, flushing, pruritus, angioedema rash, and so on might be present. With regards to the GI tract, there are nausea, vomiting, bloating, abdominal pain, and so on. Cardiovascular and or pulmonary signs are also frequent as well as bone and muscle pain. Fatigue and neuropsychiatric symptoms such as headache, brain fog, or cognitive dysfunction often lead to a significant decrease in the performance of everyday life activities.

What you can see here is a survey made by the Mast Cell Connect Registry. And this simply shows that symptoms in SM are present throughout all subtypes of SM, showing that in indolent SM and smoldering SM, combined as indolent subforms, symptoms are as frequent as an advanced phase disease.

Usually, patients with SM do have reduced mental and physical activity. This translates into this mental and physical component score, which is much worse as compared to the score of patients with other severe diseases. Like, for example, lung or colorectal cancer, as you can see here. And this directly translates into increased use of healthcare services and increased use of medications, and often a limited ability to work for patients with SM.

Thank you for listening.

Chapter 2: Diagnosis of Systemic Mastocytosis

Hello, my name is Karl Sotlar, I'm a pathologist in Salzburg, Austria, and I would like to inform you about the diagnostic criteria and the classification of SM.

According to the WHO criteria, SM can be diagnosed when the major criterion and at least one of the minor criteria are present, or in the absence of the major criterion, at least three minor criteria are present.

So, what are the criteria? We have one major diagnostic criterion. This is the presence of multifocal compact infiltrates of mast cells. That means at least 15 mast cells should be there in aggregates, detected in sections of the bone marrow, or that's important, other extracutaneous organs. So, the skin doesn't count here in this criteria. In addition, we have four minor criteria. These include the detection of more than 25% of mast cells that have an atypical morphology. They are often spindle-shaped and hypogranulated. The second minor diagnostic criterion is the de detection of a KIT codon 816 mutation, usually KIT D816V. The third one is the detection of an aberrant expression of CD2 and/or CD25 in mast cells. And the fourth is an increased serum tryptase level above 20 ng/mL. You see here in gray an addition that will come up in the next WHO classification of mastocytosis, then also other critical regions of KIT are included, and CD30 is also included as a minor diagnostic criterion.

In addition to, or for the subtyping of SM, B and C findings have been defined, as shown here. The B findings are important for the diagnosis of smoldering SM, while the C findings are important for the diagnosis of aggressive SM. B findings show you that there's an increased mast cell burden in the body without organ impairment. C findings are a consequence of mast cell infiltration in various organs, like the bone marrow, liver, the spleen, the skeleton, or the GI tract with organ impairments.

On the next slide, you see on the right the defined SM subtype. So, in the current classification, it's indolent SM, smoldering SM, aggressive SM, SM with an associated hematologic neoplasm, so SM-AHN, and mast cell leukemia. The indolent SM is diagnosed when the criteria are fulfilled. If we have two or more B findings, smoldering SM can be diagnosed. Aggressive SM is diagnosed when at least one C finding is present. AHNs, hematological neoplasms, are defined or are diagnosed as defined by the WHO. For mast cell leukemia, you need to have at least 20% of mast cells in a bone marrow aspirate smear.

Thank you for your attention.

Chapter 3: Presentation of Systemic Mastocytosis

Hello. My name is Karl Sotlar, and I'm a pathologist from Salzburg, Austria. I would like to show you, now, how SM is presenting, by cyto- and histo- pathology.

Let's start with the cytomorphology of mast cells. You see here on the left, a normal mast cell with a lot of metachromatic granules and you see various forms of atypical mast cells, atypical mast cells type one, type two, and the metachromatic blast. As you can see, these atypical mast cells are frequently spindle-shaped and are hypogranulated, and they have atypia in the nuclei. Sometimes there are bilobed or multinucleated forms present in mastocytosis.

In histomorphology, the diagnostic hallmark is the so-called compact mast cell infiltrates. It does not only contain mast cells, which are spindle-shaped in this case, but also other cell types, like lymphocytes and eosinophilic granulocytes, are present. This is the major diagnostic criterion of SM.

This picture shows you various subtypes of SM. In the upper-left, atypical case of indolent SM, with two compact mast cell infiltrates, which in this magnification look like granulomas. In aggressive SM, ASM, we see osteosclerosis and a lot of fibrosis. These are large, confluent, compact mast cell infiltrates. You see only a very few fat cells and remaining hematopoiesis. In the lower-left, you see a case of SM with an associated hematologic neoplasm. In the upper left, there's a compact mast cell infiltrate, and in the lower right, there's infiltration of a myeloid neoplasm. And [also] in the lower left, there's a case of mast cell leukemia. This is a bone marrow aspirate smear, and you see almost all of these cells are atypical mast cells, and in the center there's a multinucleated, highly atypical mast cell, in a case of mast cell leukemia.

It is of utmost importance that the hematopathologist performs immunohistochemistry in the diagnosis of SM. There are markers like tryptase and CD117 that are expressed in normal and neoplastic mast cells, and that help to enumerate mast cells. In the upper left, you see the picture you already know, with two compact mast cell infiltrates, and in addition, you see that there's an increase in interstitial mass cells. Please be aware that in 20 or 25% of cases, the compact mast cell infiltrates are missing, and it's very hard without immunohistochemistry to appreciate this interstitial infiltrate. Immunohistochemistry also is a minor diagnostic criterion, and the aberrant expression of CD25 and CD30 serve as minor diagnostic criteria, as does the detection of KIT mutations.

We can discriminate between cases in which the KIT mutation is detectable only in mast cells, which is typical for indolent SM, if we have involvement of other hematopoietic lineages by KIT. This is often the case in SSM or ASM, aggressive SM, and the detection of additional mutations like SRSF2, ASXL1, RUNX1, and so on, is a sign of an associated hematologic that is then myeloid neoplasm. And of course, detection of this mutation is a minor diagnostic criteria.

As is an elevated serum tryptase level, please be aware that, like with the compact mast cell infiltrates, about 30% of SM patients exhibit normal tryptase levels.

And please be aware that in SM-AHN, the great majority of associated hematologic neoplasms are myeloid malignancies. Most of them come from the MDS/MPN overlap categories, and the most frequent single type of associated hematologic neoplasm is CMML, chronic myelomonocytic leukemia.

Thank you for your attention.

Chapter 4: Systemic Mastocytosis: Diagnostic Challenges

Juliana Schwaab, MD: Hello, my name is Juliana Schwaab. I'm a hematologist based in Mannheim, Germany, and together with Professor Sotlar from Salzburg, I'm going to present two clinical cases of SM with a rather difficult diagnostic approach.

Karl Sotlar, MD: Hello, my name is Karl Sotlar, and as Juliana said, I'm a pathologist in Salzburg, Austria.

Juliana Schwaab, MD: We start with a 70-year-old female patient who presented with thrombocytosis and discrete leukocytosis. Together with these lab findings, she complained of some pruritus, and we suspected a myeloproliferative disorder, maybe essential thrombocythemia or even myelofibrosis. And therefore, we performed bone marrow analysis.

Karl Sotlar, MD: Yeah, and the striking morphological picture here is a slight increase in cellularity in this bone marrow with these predominating clusters of partly atypical megakaryocytes, which are appreciated by immunochemistry with antibodies against CD42. In addition, we see an increase in tryptase-positive mast cells in the lower left part of the picture. And you can see that most of these mass cells are spindle-shaped, and in the lower-right, show an upper-end expression of CD25.

So, this is a case which is highly suspicious for SM, which doesn't show compact mast cell infiltrates in this bone marrow trephine biopsy specimen. Because of the suspect of SM, we performed molecular studies and we were able to detect KIT D816V with a very low allele frequency of 0.1%, perfectly fitting to the only minor bone marrow infiltration of mast cells. So, the diagnosis in this case is KIT D816V positive SM-AHN, which in this patient is a bone marrow mastocytosis with associated essential thrombocythemia.

Juliana Schwaab, MD: So, with that we would like to come back to case number two, which was a 63-year-old male. He presented with night sweats, a significant weight loss, diarrhea, and ascites to his GP and blood counts revealed significant leukocytosis with blast increase and eosinophilia. And the serum tryptase of value was elevated to 840 µg/L. Bone marrow trephine revealed the following:

Karl Sotlar, MD: Yeah, this is a complex morphology. We see a highly hypercellular bone marrow with a lot of immaturity with blasts through it and even blast cells. In the Giemsa stain we see an increase and even compact infiltrates of round mast cells that can be nicely appreciated because of their metachromatic granules. Of course, in the lower left, they show an expression of tryptase.

But in addition, there's another neoplasm in this case, which is indicated by the expression of myeloperoxidase, which is not expressed in neoplastic mast cells. So, we have an MPO positive blast population, and we have in the bone marrow aspirate smear more than 20% mast cells and the diagnosis as a consequence is an SM-AHN with an aleukemic mast cell leukemia and an associated acute myeloid leukemia. This case did not show the KITD816V mutation.

Juliana Schwaab, MD: And here diarrhea and ascites as well as the significantly elevated serum tryptase value now perfectly fit into this case of otherwise acute myeloid leukemia without these symptoms usually present.

Karl Sotlar, MD: Thank you for your attention.

Juliana Schwaab, MD: Thank you for watching.

Chapter 5: Treatment Evolution in ​Advanced Systemic Mastocytosis​

Hello. My name is Deepti Radia. I'm a Consultant Hematologist at Guy's and St Thomas' Hospital in London. We're going to walk through the treatment evolution in advanced SM in the next few minutes.

So as you'll all be aware, advanced SM has three categories of mastocytosis in it. These are patients with aggressive SM, who meet the criteria for ASM by having C-findings, one or more C-findings. Patients with SM-AHN, an associated hematological neoplasm, make up the majority of this group; more than 70%, who have SM with an additional neoplasm, most likely to be myeloid in origin, and mast cell leukemia, where these patients need to have more than 20%, [in the] smears, of mast cells.

Overall, within this category of advanced SM, we know that the prognostic outcome is poor, and within these subcategories, patients with mast cell leukemia have the poorest overall survival, followed by those patients with an SM-AHN. But within this category, this is variable dependent upon the AHN, and those that do most favorably are the patients with ASM but again, overall prognostic survival for these patients is poor.

So where are we with the treatment of advanced SM at this point in time? Looking at the three subcategories I'm going to talk about the aggressive SM and mast cell leukemia in the same context. If you have patients with ASM or mast cell leukemia, if possible, to consider them for a clinical trial. Now, clinical trials currently with potent directed c-Kit inhibitors, which has been shown to be efficacious and beneficial for all patients with advanced SM, but in particular with those with ASM and MCL.

Second line therapy would be targeted TKIs that are available, and midostaurin currently is available in Europe and internationally and avapritinib in the USA. Midostaurin will de bulk and is disease-modifying. Cladribine has been used to de bulk. It is a cytotoxic agent, it is not a targeted agent, [used] where rapid de-bulking, reducing spleen size or high disease bulk is required. For aggressive SM patients who are negative in c-Kit mutation,or are positive eosinophilia with the FIP1L1 mutation need to be treated with imatinib. And pegylated interferon is available, not used as frequently these days for ASM, but can make a difference for those patients that have bony disease.

An allogeneic transplant should be considered for all patients if we're able to get the SM under some sort of remission and they have appropriate donors.

For patients with SM-AHN it's slightly different. We need to integrate the histological reports, as you are aware, and decide which one of these two diseases is causing the end organ damage or the organopathy and treat the appropriate one. So, you may treat the AHN first and then move on to treat the SM. And you may have syncopated treatment if both diseases are in remission or if appropriate, a bone marrow transplant may be considered.

With consideration of the new trials. I just need to walk you through the response criteria. So, the Valent treatment response criteria were used prior for the first trial for midostaurin, and these looked at major responses, partial responses, and no responses looking at the C-findings. And in order to have a major response, you needed to have a complete disappearance of the mast cells, normalization of the tryptase. And then looking at clinical responses, partial responses was 50% of regression of mast cell disease, and then minor response and no response. These were fairly blunt, but these were the first criteria that we used and were helpful in evaluating the efficacy of the medications.

The response criteria moved forward with our understanding of the diseases and the complexity of the spectrum of patients with advanced SM and the International Working Group criteria were developed to actually quantify those nebulous findings. So, the degree of anemia, the degree of transfusion dependency, the degree of thrombocytopenia and whether or not platelets were required, were important parameters. The non-hematological parameters, like the amount of ascites, the requirement of medical treatment of ascites and splenomegaly was important, and these needed to be quantified. So, these were then developed in order to help with the quantification, looking at the new TKIs.

And currently, we've seen for the first time with the use of avapritinib that mast cells can be cleared completely, and you can get complete remission, a pathological remission with no evidence of the SM either within the bone marrow, complete recovery of the tryptase, getting lower than 20 milligrams. However, the patient may still not have a complete hematological response as required. This could either be due to the TKI or the possibility of the AHN component, which exists in most of these patients. So, you'll find these response criteria have evolved over time and will continue to develop in order for us to fully evaluate newer TKIs as they are developed.

Thank you.

Chapter 6: Established and Emerging Therapies in Advanced Systemic Mastocytosis

Hello, my name's Deepti Radia, I'm hematology consultant at Guy's and St. Thomas' in London. We're going to walk through the established and emerging therapies in advanced SM in the next few minutes.

We'll start off with midostaurin, which is a broad-spectrum multi-kinase inhibitor with activity against the KIT mutation, both the D816V mutant and wild type, as well as having an effect on FLT3, PDGFR alpha/beta, and the protein kinase family members. It's demonstrated activity against mast cells, both in vivo and in vitro, and has been approved for treatment by the FDA [and] EMA for treatment of advanced SM in 2017, with a recommended dose of 100 mg twice daily with food.

This phase two pivotal trial that was reported in 2016 was the first time we were shown that TKIs make a difference in mast disease burden and bulk and overall response and survival. The trial included 116 patients, and there were 89 patients who were evaluable. The overall response rate for these 89 patients was 60%. 45% of these patients had a major response. The midostaurin was started at a dose of 100 mg twice daily, and the median overall survival for these patients across all three groups was found to be 28.7 months, with an overall survival, not reached for patients with aggressive SM. The median progression-free survival was, across the whole cohort, 14.1 months, and the waterfall plots show for the first time that we noticed that there was a decrease in bone marrow mast cell burden and a decrease in tryptase, so these were disease modifying agents improving overall survival.

Midostaurin, in terms of its side effects, has nausea and vomiting as the most commonly reported side effects, and this could be managed with treatment with antiemetics prior to ingestion of medication. Diarrhea has been reported in over half of the patients. Again, these can be managed with disease modifications, and there was a discontinuation rate of 22%, with dose reductions in 41% of patients, and they could have been re-escalated up to 100 mg twice daily. There were worsening grade 3 and grade 4 hematological AEs of neutropenia, thrombocytopenia, and anemia, and again, these led to dose reductions, discontinuations, and restarting at a lower dose was sometimes beneficial.

Avapritinib is a potent selective KIT D816V inhibitor. It's a type 1 small molecule designed to bind into the active conformations of KIT. It binds weekly to the wild-type KIT and also inhibits other KIT mutations found in exon 11, 11/17. It's been approved for treatment use in advanced SM. Again, looking at the efficacy of this based on the PATHFINDER study that was reported last year, the overall patient numbers enrolled were 62 and the interim analysis of the efficacy population made up of 32 patients. You can see here that at the overall response rate was 75%, and across the board, the patients did well, with significant decreases in bone marrow mast cell burdens and serum tryptase, and they did well regardless of prior therapy. The efficacy population continues to stay on the medication and the median progression-free survival and the median overall survival in the safety population has not been reached at this point of the data cutoff.

The common treatment AEs include peripheral edema and periorbital edema in just under half of the patients. There were GI toxicities reported of diarrhea, nausea, and vomiting in a small percentage of patients, and myelosuppression was noted in patients, up to 40% in thrombocytopenia, anemia, 19%, and neutropenia, 23%. These could be treated by the discontinuations or dose reductions, and dose reductions were in just under 70% of the patients due to the cytopenias. There was one patient reported with a grade 4 subdural hematoma, and this patient had a preexisting thrombocytopenia with a platelet count, less than 50x10^9/L, and the protocol since then had been changed in order to make sure patients had a platelet count above 50 prior to admission to trial.

Other agents used currently the treatment of SM, that are non-targeted, are cladribine, which is a cytoreductive agent. It's an off-label use. Its use is in rapid debulking of patients with large spleens and a high count and can have sustained responses. Imatinib is used and has been approved for ASM without the KIT mutation, which would be in about 5% of patients, or with an unknown c-KIT status, or in well-differentiated SM. Alpha interferon and hydroxycarbamide are used in patients with SM just to decrease the numbers but are not disease-modifying agents.

Thank you very much.

Chapter 7: Systemic Mastocytosis: Case Reviews

Juliana Schwaab, MD: Hello, my name is Juliana Schwaab, I'm a hematologist based in Manheim, Germany, and together with my co-chair Deepti, I'm going to present you two cases of SM patients and their treatment courses.

My patient is a 66-year-old male young patient who presented at his GP with symptoms like night sweats, weight loss, and diarrhea. His spleen was heavily enlarged, and he had some other concomitant diseases. The GP did a blood count, and this revealed a significant leukocytosis with monocytosis and eosinophilia, as well as slight anemia and a thrombocytopenia. Therefore, the patient was transferred to our hospital, and we did some other lab analyses, as well as bone marrow trephine. And in the histology assessment, the pathologist revealed a 15% mast cell infiltration and an associated MDS-MPN overlap syndrome, and this is in line with the excessively elevated serum tryptase value, and an increase in the alkaline phosphatase level, as well as a decrease of the albumin level.

Together with this, the patient was positive for the KIT D816V mutation, as we know, this is the disease-initiating mutation, as well as the prognostically-relevant SRSF2 mutation. The patient also had some signs of urticaria, which were histologically proven also, and his diarrhea was objectively diagnosed as a histologic infiltration of mast cells. The patient was assigned to a high-risk category using the MARS risk-score, and hydroxyurea was started due to leukocytosis with absolutely no change. Therefore, we initiated debulking therapy using cladribine over 5 days for 6 cycles, with a significant amelioration of the lab parameters. As you can see on this slide, a significant decrease of leukocytes, increase in platelets, and a decrease in alkaline phosphatase value and tryptase value.

However, as you can also see already, soon after stopping cladribine treatment, lab parameters deteriorated already, and this led to the initiation of midostaurin as kind of a maintenance therapy, using the regular dose of 25 milligrams four in the morning, 4 in the evening, as well as antiemetic prophylaxis. And here you can see that this tyrosine kinase inhibitor resulted in a rapid and sustained amelioration of lab parameters, and this, of course, again, clearly highlighting the fact that cladribine treatment is effective in debulking, but that other treatment concepts should be included shortly after stopping of cladribine. Thank you very much for listening.

Deepti Radia, MD: Hello, my name's Deepti. I'm a consultant hematologist at Guy's and St Thomas Hospital in London. I'm going to present my case with SM. This is a patient who is currently 53 years old, and was diagnosed with smoldering SM in 2011. Over the period of the next 4 years, he started to get increasing mediator symptoms and developing increasing hepatosplenomegaly with a slight rise in his ALP. In December 2014, he was admitted with an anaphylactic reaction having ingested aspirin, and the following year, he had 2 admissions for acute GI bleeding, needing intensive care support on blood transfusions as a result of multiple gastric and duodenal erosions, which responded to endoscopic laser treatment.

We decided to reevaluate him to see if he'd progressed to aggressive SM. In terms of his evaluation, he had a CT scan done, which confirmed the hepatosplenomegaly. He had also noted to have marked, enlarged intraabdominal, intrathoracic lymph nodes. He was known to have marked osteosclerosis, and he had indeterminate lung nodules, which were not mast cell-related. His bone marrow aspirate showed that he had a disease bulk of 50% clonal mast cells with the appropriate clonal markers. His cytogenetics were normal, and he had grade-one fibrosis.

At the time his tryptase had risen to 335 microns per liter, and he had a raised ALP of 181 international units per liter, and we reassessed him and named him as being aggressive SM on those grounds. We started treatment with midostaurin on a compassionate use program at a starting dose of 100 milligrams twice daily. Within 3 months, he had a good response, with the rash no longer visible and no palpable organomegaly. He continued to respond well, but by October 2018, we noticed that he was having a rise in his tryptase level, and on reassessment, his bone marrow disease bulk was 50%, as back to the start of treatment with the midostaurin.

A myeloid gene panel at the time confirmed he only had the c-KIT mutation. At that point we agreed that he'd had a clinical improvement on treatment of midostaurin for 26 months, but no change in his disease bulk. And he consented to take part in the Pathfinder trial and was consented to start on avapritinib at 200 milligrams once a day for advanced SM. The baseline values at cycle one day one showed his full blood count was pretty reasonable. His liver was palpable at 3 centimeters below the costal margin, spleen at 2 centimeters. Of note, his tryptase was now 551 micrograms per liter, and his alkaline phosphatase had been rated to 870 international units per liter.

This is his response in terms of images. So, at the baseline, you can see that he has a cutaneous widespread maculopapular rash across his torso and arms, but this is all across the front of his body, and all down his legs. His histochemistry on his bone marrow trephine shows at least a 60 to 70% disease bulk of abnormal mass cells. But you can see on CD117 and CD25, that these were pretty significant and demonstrated here. At cycle 131, which is three months down the line, he'd had a remarkable response. You can see the rash had almost cleared with the telltale sign of white hair being on a TKI. His bone marrow showed that we were unable to identify very many mast cells, he had no aggregates, and so was in a complete remission from a pathology point of view.

So, at that point in three months, he'd done extremely well. He had normal blood counts and when he was reviewed at cycle 16, he still remained in a CR. We reduced his avapritinib to 100 milligrams once daily, and his side effect of periorbital edema has improved. His counts are all normal, including his tryptase at 5 micrograms per liter, and his alkaline phosphatase, and his most recent bone marrow, still confirms he's in complete remission.

These graphs are just to demonstrate the effect of the two TKI’s on alkaline phosphatase levels. You can see from the midostaurin that his ALP level did drop. And from the avapritinib you get a spike in the ALP within the first four to six weeks, which is a treatment effect, which does normalize over time. The tryptase levels with midostaurin did reduce but did not normalize, but with avapritinib, they reduced and normalized fairly promptly. And in terms of his platelet count, he was never thrombocytopenic, but with both drugs, his platelet counts did not drop significantly below 50, and remained quite stable.

Thank you very much.

This is a verbatim transcript and has not been copyedited.

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