Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards

ASCO University
Jul 13, 2016 9:27 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

This month’s topic is led by Drs. Todd Kelley (University of Utah) and Ruben Mesa (Mayo Clinic).

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Please see attached for supplemental resources related to the case.

Comments

12931

ASCO University
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 13, 2016 9:53 AM

Patient Case #1

Age/Sex: 61 year old male from Chicago, IL. Right hand dominant Chef at a celebrated restaurant.

Medical History: Patients was found to have significant thrombocytosis at the time of Emergency Department evaluation of a transient ischemic attack presenting with right sided sensory and motor deficits. History positive for 6 months of fatigue, frequent migraines with complex auras, occasional aquagenic pruritus.

Exam: Notable for BP of 170/100 and Heart Rate of 105 BPM (regular). Spleen tip palpable

MPN Symptoms (MPN10): 18 (out of possible 100).

Labs
Hemoglobin 15g/dL
Leukocytes 12x 10(9)/L
Differential Slight neutrophilia
Peripheral Smear  Thrombocytosis, occasional giant platelets
Platelets 1100 x 10(9)/L

 

 

 

 

 

CT Head (non contrast): No hemorrhage or lesions.

Prior Treatment History/Response: Newly diagnosed. Managed initially by admission to hospital, given aspirin. Symptoms resolved within 30 minutes and released.

Co-morbidities: Hypertension, Hyperlipidemia.

Scans/Pathology:

  • Abdominal Ultrasound: Spleen slightly enlarged at 13 cm
  • Bone Marrow Aspirate and Biopsy: The bone marrow aspirate showed complete trilineage hematopoiesis without left-shifted granulocytes and without increased myeloblasts. There was no dysgranulopoiesis or dyserythropoiesis. The myeloid to erythroid ratio was in the normal range. Numerous large megakaryocytes were observed. An iron stain on an aspirate smear demonstrated the presence of storage iron with no ring sideroblasts. The bone marrow core biopsy demonstrated slight hypercellularity for age with marked megakaryocytic hyperplasia. The megakaryocytes were predominantly large in size with hyperlobate nuclei and were present in loose clusters. There was no significant reticulin fibrosis (MF-0) or osteosclerosis.
  • Image: Hematoxylin and eosin (H&E) stain of the bone marrow core biopsy (x400 magnification)
  • Relevant Markers: Calreticulin (CALR) mutation noted (52 bp deletion in exon 9).
  • Cytogenetics: 46, XY [20] metaphases

Type of Tumor: Myeloproliferative Neoplasm with thrombocytosis, essential thrombocythemia vs. primary myelofibrosis

12936

ASCO University
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 13, 2016 10:02 AM

Discussion Questions

  1. According to WHO 2016 criteria, what is the most accurate diagnosis and how do we distinguish ET from PMF in era of molecular studies? Does it matter to distinguish early primary myelofibrosis from essential thrombocythemia for management?
  2. How would we estimate this patients risk of vascular events? Risk of disease associated progression or mortality?
  3. How would you manage this patient? Would the presence of the CALR mutation alter your management? Would you use cytoreductive therapy and which agent? What would be the goal platelet count? Would you need to normalize the white count? Impact on management of co-morbidity?

12946

Todd Kelley
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 18, 2016 9:14 AM

Course Faculty Response

The pathologic findings are indicative of involvement by essential thrombocythemia (ET) in the 2016 WHO classification system and the patient meets all four major criteria for the diagnosis (Arber). The distinction between ET and early (pre-fibrotic) primary myelofibrosis (PMF) can, at times, be challenging. The current case demonstrates marked thrombocytosis (1100 x 10(9)/L) with slight age adjusted hypercellularity due to megakaryocytic hyperplasia. In contrast, the hypercellularity of early PMF is mainly due to granulocytic hyperplasia. The megakaryocyte morphologic features also point towards ET, which characteristically features large megakaryocytes with hyperlobulated nuclei, as seen here. The lack of reticulin fibrosis is also more characteristic of ET at presentation. Early PMF, even at the so-called “prefibrotic” stage, tends to display some slight reticulin fibrosis (MF-1). A type 1 mutation in the calreticulin (CALR) gene was also identified. CALR mutations in patients with ET or PMF are insertions or deletions in exon 9 of the gene which all result in a shift to the same abnormal reading frame. This results in production of a protein with an abnormal carboxyl terminus. Mutant forms of calreticulin appear to promote inappropriate signaling through the thrombopoietin receptor in megakaryocytes(Chachoua, Araki). CALR mutations are not seen in patients with polycythemia vera (PV). Type 1 CALR mutations are 52 base pair deletions and are slightly more common than type 2 CALR mutations, which are 5 base pair insertions. CALR mutations can be identified in the majority of patients with ET and PMF who lack a JAK2 V617F mutation so the finding of a CALR mutation alone is not particularly helpful for distinguishing between the two entities. When compared to ET patients with mutated JAK2, those with mutated CALR tend to have higher platelet counts (Trifa). Newer findings indicate that there are potential differences in the outcome of ET patients that may be attributable to the type of CALR mutation (type 1 vs type 2). For example, ET patients with type 1 CALR mutations may have a higher risk of myelofibrotic transformation (Pietra). However, prognostic schemes incorporating this information are not currently in use.

12951

Ruben A. Mesa, MD
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 18, 2016 9:39 AM

Course Faculty Response

Question 1
The case in question highlights the current transition in thinking in the World Health Organization diagnostic criteria to further refine the differences between those individuals with early primary myelofibrosis versus those with essential thrombocythemia (Barbui).  These criteria have specifically been somewhat slow in adoption due to their heavy reliance on histologic features in distinguishing between these two entities. I would emphasize that these two entities have a distinct and natural history as has been identified in prior efforts by Barbui (Carobbio)  from those with early myelofibrosis having a much higher progression rate to overt myelofibrosis in acute leukemia versus those with essential thrombocythemia. It is key to recognize that in addition to histologic changes, there additionally tend to be clinical features indicative of more early myelofibrosis including a leukoerythroblastic blood picture, changes in LDH, splenomegaly, differences in the symptomatic profile. In the case presented, this individual lacks any of these features as well as histologic features and confirms the diagnosis of essential thrombocythemia. The main impact is really on prognosis and long term natural history and it can be argued at the current time would not alter our initial approach to therapy, which is primarily around prevention of thrombosis and bleeding.  

Question 2
Estimation of risk of vascular events in patients with essential thrombocythemia historically has focused on two features, age over the age of 60 and prior thrombotic events, and this individual would qualify for being high risk on both accounts between his age of 61 and  the prior transient ischemic attack (the equivalent of a “vascular event”). In addition, in the IPSET score (Barbui), it has been identified that leukocytosis is an additional risk factor in addition to age and prior venous thromboembolic event, which should be considered. This individual would similarly be at high risk given this new scoring system. These risk scores are primarily impactful regarding predicting risk of thromboembolic events.  

Question 3
This patient has the calreticulin mutation (CALR), which is then identified in general for those with essential thrombocythemia to have lower risk of thrombotic events (Alvarez-Larran). However, there clearly are individuals who have CALR mutated essential thrombocythemia who do indeed have vascular events and the other risks that the patient experiences should not be ignored. Given this patient’s age, presentation with a TIA and leukocytosis, I probably would not alter the appropriate decision to use cytoreductive therapy. This individual would be managed according to current ELN Guidelines (Barbui) in terms of shooting for a platelet count of under 400,000, frontline therapy would be at the current time, cytoreduction with hydroxyurea in a 61-year old individual with a goal of normalizing the white count and the platelet count with anagrelide or pegylated interferon alpha as second like therapy. All of this would be in addition to the utilization of low dose aspirin in patients who are not aspirin allergic. The patient would remain on aspirin but would be tested for any degree of acquired Von Willebrand disease in the setting of significant thrombocytosis. Concurrent with aspirin and cytoreduction, one would aim to have control of the hypertension and hyperlipidemia in accordance with standard recommendations for those individuals with cerebrovascular disease. 

12956

ASCO University
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 18, 2016 9:54 AM

Patient Case #2

Age/Sex: 64 year old female from Marin County, CA. Left hand dominant enologist at a Sonoma winery.

Medical History: Presents for evaluation of 6 months of worsening fatigue, night sweats, and weight loss. Polycythemia Vera was diagnosed in 2002 and she arranged this consultation to see if her disease was “worse”

Exam: Notable for mild pallor, some cachexia suggested by prominent decreased muscle mass in the shoulder girdle. Spleen palpable 15 cm below the left costal margin in the mid clavicular line.

Labs
Hemoglobin: 8.7 g/dL
Leukocytes: 26 x 10(9)/L
Differential:  Neutrophilia, 2% metamyelocytes, 1% myelocytes, 1% blasts
Peripheral Smear: Leukoerythroblastic smear, dacrocytes, nucleated red blood cells, occasional blasts and other immature myeloid elements.
Platelets: 110 x 10(9)/L

MPN Symptoms (MPN 10): 42 (out of 100)

Prior Treatment History/Response: Polycythemia vera initially managed with aspirin 81mg/day, phlebotomy (goal hematocrit <45%), and hydroxyurea. In 2006 when commercially available she tested positive for the JAK2 V617F mutation at 60% allele burden. She no longer required phlebotomies after 2010 and discontinued hydroxyurea in 2015 on basis of malleolar ulcer on the left leg. She had remained solely on aspirin since stopping the hydroxyurea.

Co-morbidities: Appendectomy (age 30), Tubal Ligation (age 30), DCIS of left breast age 51.

Scans/Pathology:

  • Abdominal Ultrasound: Spleen significantly enlarged at 27 cm
  • Bone Marrow Aspirate and Biopsy: The bone marrow aspirate was aspiculate, paucicellular and hemodilute. The bone marrow core biopsy demonstrated very prominent myelofibrosis. Megakaryocytes were small with hyperchromatic nuclei and were present in occasional clusters. Erythroid elements were relatively reduced compared to granulocytic elements. Sunusoids were dilated and there was slight osteosclerosis. A reticulin stain showed marked reticulin fibrosis (MF-3) and a trichrome stain demonstrated focal collagenous fibrosis. An immunohistochemical stain for CD34 performed on the core biopsy showed 5-10% CD34-positive immature cells in the bone marrow.
  • Image #1: Hematoxylin and eosin (H&E) stain of the bone marrow core biopsy (x400 magnification).
  • Image #2: Reticulin stain of the bone marrow core biopsy (x400 magnification).
  • Relevant Markers: JAK2 V617F mutation at 54% allele burden. Presence of ASXL1 mutation by corresponding next gen sequencing panel.
  • Cytogenetics: 46, 20q-, t(1;7) XX [20] metaphases

Type of Tumor: Post PV myelofibrosis.

12961

ASCO University
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 18, 2016 9:57 AM

Discussion Questions

  1. How do we confirm progression from PV to Post PV myelofibrosis? Do molecular features play a role in determining progression?
  2. How do we calculate risk of mortality for this patient on basis of clinical features? Marrow features? Molecular features?
  3. How would molecular features impact your decisions regarding management? Medical therapy vs. allogeneic stem cell transplant?

12976

Todd Kelley
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 22, 2016 10:01 AM

Course Faculty Response

The bone marrow demonstrates marked reticulin fibrosis and focal collagenous fibrosis with elevated immature CD34 positive cells (5-10%), confirmed by immunohistochemical staining. The patient has a history of polycythemia vera (PV) diagnosed in 2002. In this context, the bone marrow morphologic findings are best classified as post-PV myelofibrosis (Arber). It is necessary to understand the clinical context of the pathologic findings in order to appropriately classify this process because the findings, in isolation, are indistinguishable from other myeloproliferative neoplasms with myelofibrosis. The increased numbers of immature cells confirm that the process is entering a more aggressive phase. A JAK2 V617F mutation was identified with an allele frequency of 54%. In PV patients, a high JAK2 V617F variant frequency (>50%) has been associated with myelofibrotic transformation in some studies (Passamonti, Cerquozzi). The presence of a mutation in the ASXL1 gene, encoding an epigenetic and transcriptional regulator, provides additional molecular confirmation of adverse prognosis. ASXL1 mutations are associated with poor prognosis across the spectrum of myeloid malignancies.

12981

Ruben A. Mesa, MD
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 22, 2016 10:09 AM

Course Faculty Response

Question 1
Progression from PV to post PV myelofibrosis relies not only on a clear increase in intramedullary fibrosis, but also the development of progressive clinical features including two of the following: anemia or sustained loss of either phlebotomy or cytoreductive treatment for erythrocytosis, a leukoerythroblastic peripheral blood picture, increasing splenomegaly or development of weight loss, night sweats or unexplained fevers (Barosi). At the current time, it is not clear that there is a molecular profile differentiation between PV and post PV myelofibrosis. There is a suggestion that there is a greater accumulation of other somatic mutations along the process of progression, however this is not yet sufficiently defined to be included as a progression criteria. It is not clear it solely changes in the allele burden in JAK2-V617F play a clear role in disease progression.

Question 2
There currently are many prognostic scoring systems for myelofibrosis.  The majority of these prognostic scoring systems have focused primarily on patients with primary myelofibrosis. Although they have been utilized interchangeably for those individuals with post PV myelofibrosis, it is unclear whether this remains an accurate decision (Passamonti). In part, the current prognostic scores for myelofibrosis include anemia and red cell transfusion dependence as important negative prognostic markers and these frequently are not as likely to occur in the setting of post PV myelofibrosis. Additional risk factors which occur independent of primary myelofibrosis versus post PV myelofibrosis are first marrow features that are suggestive of further movement toward acute leukemia such as increased blasts; additionally, molecular features which seem to be of adverse prognostic significance include a variety of additional somatic mutations, such as ASXL1, EZH2, IDH1 &2, amongst others. Patients with primary myelofibrosis who lack a driver mutation such as JAK2-V617F, CALR or MPL appear to have a more adverse prognosis (Vannucchi). This is at last relevant in this case in that very few patients with post PV myelofibrosis would be triple negative given the high prevalence of the JAK2 mutation.  

Question 3
Molecular features have not yet made a major impact on the medical therapy of individuals with myelofibrosis; however, at an increasing rate adverse additional somatic mutations in these cases are considerations in terms of risk and can impact the selection of stem cell transplantation. This individual has the ASXL1 mutation, which has been proven in a variety of parallel prognostic series to have an adverse outcome (Vannucchi). In addition to this, this individual would be considered a high risk on the basis of anemia, significant leukocytosis, blasts in the peripheral blood, significant constitutional symptoms as well as these adverse molecular features. All of these factors together would emphasize the importance of a consideration of stem cell transplantation as an option. Initial medial therapy likely would consist of JAK inhibition, likely with ruxolitinib at 10 mg twice a day, while identification of donors and patient’s appropriateness for transplant was being considered. Alternative frontline clinical trials for patients with high risk myelofibrosis with anemia would also be a consideration.

12991

Todd Kelley
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 27, 2016 12:58 PM

Course Faculty Summary

Summary Case 1 
1.The pathologic distinction between true ET and early-PMF may be challenging but should be made due to the difference in outcomes.
2.CALR mutations are seen in both ET and PMF patients but are not seen in patients with PV.
3.Evidence is emerging that the type of CALR mutation (type 1 versus type 2) has additional prognostic significance.

Summary Case 2
1.The patient has post-PV myelofibrosis.  The pathologic features of marked myelofibrosis with collagen deposition and increased immature CD34 positive cells are indicative of disease progression.
2.The JAK2 V617F mutant allele burden is high (>50%) and there is also a mutation in ASXL1. The former has been associated with myelofibrotic transformation and the latter has generally been associated with poor prognosis in patients with myeloid malignancies.

12996

Ruben A. Mesa, MD
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 27, 2016 1:02 PM

Course Faculty Summary

Summary Case 1

1. High risk patient with essential thrombocythemia presenting with a thrombotic event, CALR mutated with additional risk factors of leukocytosis, significant thrombocytosis.

2. High risk on the basis of IPSET current risk scores, including age, leukocytosis and presentation with a thromboembolic event.

3.  Although CALR mutated essential thrombocythemia may have a decreased risk of vascular events, it remains unclear whether we should alter our historic guidance regarding use of cytoreductive therapy in this population and in this case, where there clearly is high risk, cytoreduction should proceed as otherwise would be planned with goals of normalization of the platelet count and therapy tolerability. 

Summary Case 2

1.  Patients with high risk post PV myelofibrosis confirmed by progressive features both of the marrow with increasing fibrosis corresponding with worsening anemia, leukoerythroblastic blood picture, significant constitutional symptoms and massive splenomegaly.

2.  The patient has high risk features both by traditional prognostic scores such as DIPSS as well as the new MIPSS given the presence of the ASXL1 mutation.

3.  Initial management would focus on likely JAK inhibition to improve symptoms of splenomegaly and survival in a modified dose to compensate for present anemia. Clinical trials would be a consideration. Intermediate to longer term therapy would include consideration of stem cell transplant with the quality of potential donors being an important factor.

4.  Current studies show ASXL1 patients have a guarded prognosis even with that of stem cell transplant and clinical trials for transplant for higher risk patients with alternative pre-transplant management, alternative conditioning or intensified post-transplant management would be considerations.  

13001

ASCO University
Re: Myeloproliferative Neoplasms (July 2016): Molecular Tumor Boards
Jul 27, 2016 1:09 PM

Thank you to Drs. Kelley and Mesa for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments and participants can claim CME credit and 1 ABIM MOC point through ASCO University.

Please check back in mid-August for a new case in this series related to head and neck cancer.    

Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.


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