Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards

ASCO University
Sep 09, 2015 9:57 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. This month’s topic is led by Drs. Eric Duncavage (Washington University) and Mrinal Patnaik (Mayo Clinic). 

Users are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Supplemental resources related to the case are attached for reference. 

Comments

11291

ASCO University
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 09, 2015 10:00 AM

Patient Case

67 Year old female presented with painful nodular skin lesions mainly involving the face and the extremities of 6 weeks duration.  She had seen a dermatologist and prior to undergoing a skin biopsy did have basic blood tests.

Her CBC demonstrated the following:  HB 7.1, MCV 94, WBC 2.3, ANC 0.91 and platelets 17,000.  A peripheral blood smear identified 2% circulating promonocytes.  The skin biopsy demonstrated periadnexal neutrophilic inflammation with focal leukocytoclasis.  There was no morphological or immunohistochemical evidence for involvement by leukemic cells.

Her past medical history included hypertension well controlled with amlodipine and dyslipidemia for which she was on fish oil.  No significant occupational or family history.

A bone marrow biopsy demonstrated a cellularity of 10% with 70% myeloblasts.  The blasts were positive for CD13, CD33, CD34, CD41, HLA-DR and CD117. They aberrantly expressed CD7 and CD56.  There were no MDS related changes seen.  Cytogenetics reveled 46, XX, t(6;11) (q27;q23) [20].  

FISH studies identified the MLLT4-MLL rearrangement in 94% of analyzed nuclei.  Molecular studies for FLT3, NPM1 and CEBPA were negative.

A diagnosis of MLL rearranged AML was made and she received standard induction chemotherapy with idarubicin 12 mg/m2 and cytarabine 100 mg/m2 (3+7). She was also started on prednisone for her skin rash.

ASCO University
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 09, 2015 10:01 AM

Discussion Questions

  1. What is the differential diagnosis of skin rashes that precede or accompany a diagnosis of acute myeloid leukemia?  What particular dermatological condition does this patient have?  How would you treat it?
  2. What is the prognostic significance of the MLL gene rearrangement in AML? 
  3. What is the significance of a hypocellular acute leukemia presenting with a low white cell count?

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Travis John Osterman, DO, MS
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 10, 2015 12:00 PM

Thanks so much for posting this case.  I'll try to tackle the first question. 

What is the differential diagnosis of skin rashes that precede or accompany a diagnosis of acute myeloid leukemia?  What particular dermatological condition does this patient have?  How would you treat it?

I think it's probably helpful to differentiate skin findings in AML into primary and secondary findings.  Primary findings can include leukemia cutis and infiltration by myeloid sarcoma. Secondary findings can result from the cytopenias caused by marrow infiltration: anemia->pallor, thrombocytopenia->petechiae, DIC->eccymosis, etc.

With no malignant cells identified and periadnexal neutrophilic inflammation seen, this presentation seems most consistent with leukemia cutis (LC).  As for treatment, I believe initial treatment for LC is standard induction.  It may, along with cytogenetics, influence the decision of whether or not to pursue transplant after CR-1 as LC has a higher relapse rate.

References

How I treat extramedullary acute myeloid leukemia (Bakst, et al. 2011)

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Grzegorz S. Nowakowski, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 10, 2015 1:04 PM

Very informative case with nice FISH photos. It looks like the patient was started on standard induction therapy, I would agree with this. Considering poor outcome of patients with MLL rearrangements, Dr. Osterman's question regarding role of transplant in CR1 is excellent one. I assume the patient would be a candidate for allo in CR1 if matched related donor is found. Would you consider matched unrelated donor transplant as well considering high risk of relapse? Is MLL rearrangement associated with leukemia cutis, and if so what is the proposed mechanism? 

 

Mrinal M. Patnaik
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 12, 2015 2:20 PM

Course Faculty Response

Thank you for the questions Dr. Nowakowski. MLL rearranged AMLs’ are in general associated with poor outcomes, with median OS < 12 months.  Hence in these patients, provided that an optimally matched donor is identified and as long as the hematopoietic stem cell transplant co-morbidity index is acceptable, allogeneic stem cell transplant in CR1 would be the best therapeutic intervention.  In this case, the patient had no matched sibling donors and hence a matched unrelated donor search (including double umbilical cord blood units) was undertaken.

In general, the blasts in AML with MLL rearrangements tend  to be CD34 negative and may express markers of monocytic lineage including CD11b, and CD64.  Immature monocytes, including promonocytes and monoblasts do tend to extend out in to the extramedullary compartment and hence there is a higher incidence of extramedullary disease such as; leukemia cutis, gingival infiltrates and CNS involvement.

 

Eric James Duncavage, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 14, 2015 9:48 AM

Course Faculty Response

I agree with Dr. Patnaik’s response to Dr. Nowakowski’s questions.  I would add that that it is not well understood why monocytic/monoblastic leukemias, including those with MLL gene rearrangements,  have a higher tendency to involve extra medullary sites such as the skin.  Leukemia cutis may be difficult to diagnosis and flow cytometric evaluation can be challenging in skin specimens.  Immunostains for monocytic markers including CD68, lysozyme, and CD4 in addition to myeloid associated antigens including myeloperoxidase and CD33 may be useful in establishing a diagnosis of leukemia cutis.

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Rekha Chandran, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 11, 2015 5:15 PM

I will attempt to answer questions 2 and 3.

2. Prognostic significance of MLL rearrangement in AML:  This subset of AML falls under the WHO classification of AML with recurrent genetic abnormalities. The MLL gene on chromosome 11 can have multiple partner genes e.g on chromosome 6,9,10 , 19 and several more. The prognosis varies depending on the partner gene for MLL ( more than 50 described). While t(9;11) is the commonest and would place the patient in intermediate risk category, other MLL rearrangements  move it to the unfavorable category. Interestingly MLL rearrangements are more common in individuals younger than 60yr ( our patient is older than 60yr),  and those with therapy related AML rather than de novo AML. It also tends to have a monocytic association which our patient has.

In terms of OS: A comparison is as below

t-AML- median 2.5 months

de novo AML-MLL- 10 months

de novo intermediate risk AML- 13 months

good risk t(8;21), inv (16) - 40 months

( Blood Oct 1, 2003, Schoch)

In terms of outcomes after transplantation, a recent paper suggested that MLL partner translocation affects survival and that transplantation in CR1 may be better( Leukemia 2015 June, Pigneux). In this study, t(6;11) which our patient has , t(10,11) and transplantation in CR 2 were adverse factors. The 2 yr OS for t(9;11) after transplant was 64%(+/-6%) versus 24%(+/-11%) for t(6;11).

 

3. Significance of hypocellular presentation of acute leukemia: to the best of my knowledge outcomes do not differ for such a presentation. It does make one think along the lines of antecedent underlying hematologic disorder such as MDS or myelofibrosis which would imply worse outcome. However an analysis of patients from the MDACC database did not find any difference in survival ( Hematologica 2012 Al-Kali)

Gary Spitzer, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 15, 2015 10:31 AM

in recomending allogeneic transplant for leukemia subtypes whose prognostic outcomes varies by a molecular marker , before resorting to such toxic and expensive procedures as transplant ,  we should be more criticial of the data

this transplant study was only in a subset of these patients , those who acheived a complete remission

what was the complete remission rate in this group i understand it is low contributing significantly to the poor survival , what was the median time to trasnplant , is there a landmark analysis of patients treated conservatively in remission that a true contribution of transplant to outcome can be discerned

with this new understanding of molecular biomarkers we must use them backed by significant data for clinical decision making

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Kamran Alimoghaddam, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 12, 2015 1:28 PM

Although conventional chemotherapy with 7+3regimen and then allo-HCT is prefered option but if patient don't have suitable donor or can not tolerate HCT

induction and cosolidation with demethylating agents is an alternative.

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Mrinal M. Patnaik
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 14, 2015 9:54 AM

Course Faculty Response

  1. Skin rashes that precede or accompany a diagnosis of AML have a broad differential.  If the lesions are painful and vesicular, one should consider conditions like herpes simplex or herpes zoster. If they are maculo-papular or plaque like, leukemia cutis (leukemic infiltration of the skin) is high on the differential. This is common in AML sub types with monocytic differentiation.  Sweets syndrome- or febrile neutrophilic dermatosis is a condition characterized by fever, neutrophilia, tender well demarcated nodules or plaques with dense neutrophilic infiltration seen on skin biopsy specimens. Neutrophilic eccrine hidradenitis (NEC) is a complication related to the AML and can often be seen after initiation of induction chemotherapy.In this patient the periadnexal neutrophilic inflammation was thought to be more in line with NEC. She was started on corticosteroids with a good response.
  2. MLL (mixed lineage leukemia) is a gene located on 11q23 and can be seen in ~ 10% of patients with acute leukemia (both AML and ALL, especially common in therapy related myeloid neoplasms). MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoiesis and embryonic development.  The MLL gene can be amplified, deleted or translocated in AML.  It is in general associated with a very poor prognosis. The t(6;11) gives rise to the MLL-MLLT4 fusion oncogene which can be detected by FISH studies and RNA seq.
  3. No additional commentary.

11356

ASCO University
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 14, 2015 9:56 AM

Patient Case Update

A day 14 bone marrow demonstrated residual disease. She received salvage chemotherapy with mitoxantrone + etoposide.  Due to persistent disease she was referred to the individualized medicine clinic.  A bone marrow aspirate was obtained and sent for next generation sequencing (NGS) and RNA sequencing (RNA seq).

The following results were obtained.

  1. MLL-MLLT4 fusion
  2. MLL PTD (exon 2-8)
  3. DNMT3A V809fs*2
  4. IDH2 R140Q
ASCO University
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 14, 2015 9:57 AM

Discussion Questions

  1. What is the prognostic relevance of these findings? 
  2. Of these, which genetic change should be therapeutically targeted for best patient results?

 

11346

Eric James Duncavage, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 14, 2015 9:59 AM

Course Faculty Response

  1.  Leukemia cutis and acute febrile neutrophilic dermatosis (Sweet’s syndrome) are both cutaneous lesions associated with acute leukemia.  While leukemia cutis cells are composed of immature blasts, Sweet’s syndrome is composed of mature polymorphonuclear leukocytes.  In some cases, leukemia cutis and Sweet’s syndrome may co-occur.
  2. MLL (now known as KMT2A) gene rearrangements represent about 10% of acute leukemia.  MLL is one of the most promiscuous genes involved in rearrangements, with over 100 reported partner genes, however, In AML the World Health Organization (WHO) 2008 guidelines recognize only the t(9;11)(p22;q23);MLLT3-MLL rearrangement as a special subtype.   This case would therefore be best classified as an AML, not otherwise specified.  In general the blasts in AML cases with MLL rearrangements tend to be CD34 negative and may express markers of the monocytic lineage including CD11b, and CD64.  MLL-rearranged AML may also express lineage infidelity, including expression of B-cell markers such as CD19 or CD79.  Such cases are best classified as ‘mixed phenotype acute leukemia with t(v;11q23); MLL rearranged;.
  3. While hypocelllar myelodysplastic  syndrome (MDS) represents about 10% of MDS cases, hypocellular AML is rare and is thought to have a more aggressive clinical course (PMID: 8795690)

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Gary Spitzer, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 15, 2015 10:45 AM

as you can see many patients do not make remission or do not live long enough to make transplant particularly unrelated

please see graph attached

therefore the survival of those alive at say 4 months the time it usually takes to get to transplant and in remission,  unselected for co morbidities maybe very close to the reported registry study of transplantation

just a plea for more critical research to accapt a biomarker

Attachment: 

https://connection.asco.org/sites/asco_connection/files/mll%20aml%20survival.JPG
Attachment:
Mrinal M. Patnaik
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 16, 2015 11:00 AM

Course Faculty Response

Dr. Spitzer-  I agree with you that we clearly need rigorous, prospective and preferably randomized data on the role for allogeneic stem cell transplant in MLL rearranged AML.   There currently is no landmark analysis.  Also, as you said a large number of these patients don’t make it to transplant due to primary induction failure.  At this point, all we have is retrospective data.  In a recent publication (Pigneux et al Leukemia 2015), a more favorable outcome was reported in patients receiving an allogeneic hematopoietic stem-cell transplantation. From 2000 to  2010, they identified 159 patients with 11q23/MLL rearranged AML allografted in first complete remission (CR1, n=138) or CR2, mostly corresponding to t(9;11), t(11;19), t(6;11) and t(10;11) translocations. Two-year overall survival (OS), leukemia-free survival (LFS), relapse incidence and non-relapse mortality were 56±4%, 51±4%, 31±3% and 17±4%, respectively. The outcome differed according to 11q23/MLL rearrangement, being more favorable in patients with t(9;11) and t(11;19) compared with t(10;11) and t(6;11) (2-year OS: 64±6% and 73±10% vs 40±13% and 24±11%, respectively; P<0.0001). Multivariate analysis for OS identified t(6;11), t(10;11), age>40 years and CR2 as unfavorable features, whereas t(6;11), t(10;11), CR2 and the use of reduced-intensity conditioning regimen affected poorly the LFS.  Till prospective data is available, most transplant centers do consider allogeneic HCT for patients with t(6;11).

11391

Kamran Alimoghaddam, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 15, 2015 11:27 AM

Flt3 inhibitors showed some activity in infants with MLL rearrenged ALL. Also histone demethylase showed in vitro and in vivo activity against MLL rearrenged experimental models. 

Prsence of both DNMT and IDH mutation sensitize leukemic cells to hypomethylating agents so use of Azacythidin is reasonable in this case.

Mrinal M. Patnaik
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 16, 2015 11:01 AM

Course Faculty Response

Dr. Alimoghaddam-  Thank you for your interpretation of the molecular studies. We will shortly be discussing the functional and therapeutic impact of these mutations seen in this patient.

11421

Eric James Duncavage, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 18, 2015 9:11 AM

Course Faculty Response

The evaluation of a day 14 bone marrow biopsy is an important prognostic indicator in AML.  In patients who respond to chemotherapy, the bone marrow will show near complete chemoablation with an overall cellularity of <10%; blasts will in general constitute <5% of the cells.  

Recently next generation sequencing (NGS) ‘leukemia panels’ have become a popular means by which to evaluate patients for multiple somatic mutations.  Depending on the composition of the panel, a diverse spectrum of mutations including rearrangements, amplifications, and deletions, in addition to single nucleotide variants may be discovered.  An important consideration when using such panels on a day 14 marrow is that sensitivity of the gene panel will be limited by the blast percentage.  In general 5-10% blasts should be present to ensure adequate detection of variants.  

Four mutations were detected in this case.  The MLL-MLLT4 fusion is discussed above.  MLL-partial tandem duplications are generally found in cytogenetically normal AMLs and have been associated with reduced overall survival.  The DNMT3A gene is involved in maintenance of DNA methylation and is an important epigenetic modifier.  The exact targets of the mutated DNMT3A gene in AML are unknown.  The most common DNMT3A mutations involve position R882.  This particular mutation, V809fs*2, has not been previously reported in leukemia and its exact functional consequence is unknown. The IDH2 R140Q variant occurs in a known recurrently mutated hotspot within the gene and results in increased levels of 2-hydroxyglutarate, leading to dysregulation of DNA methylation.  The prognostic significance of IDH2 mutations is unknown.

IDH2 mutations may be targeted by chemotherapy.

 

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Mrinal M. Patnaik
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 18, 2015 9:16 AM

Course Faculty Response

  1. The adverse prognostic impact of the MLL-MLLT4 (AF6) fusion oncogene has been discussed above. The MLL rearrangement in this case results in an internal tandem duplication of exons 2-8 and an in-frame fusion between MLL-MLLT4.  The MLL PTD (partial tandem duplication) is seen in ~5% of AML patients and results in duplication of exons 3-11 and is associated with a poor prognosis.

    DNMT3A codes for DNA methyltransferase 3 and plays a major role in methylation (epigenetic regulator).   The frequency of this mutation in AML varies from 9-30% and these mutations are associated with poor outcomes.  Although hypomethylating agents ( HMA) may have activity in patients with DNMT3A mutations; this particular mutation that the patient has already inhibits DNMT3A, limiting the utility of these drugs (HMA).

    IDH2 mutations impact the citric acid cycle and result in the production of an onco metabolite- 2-hydroxyglutarate, which in turn is thought to suppress TET2 and affect methylation (epigenetic regulation).   These mutations can be seen in 5-20% of patients with AML and their prognostic effect in the absence of FLT3 mutations is somewhat controversial.

  2. The IDH2 mutation can be best targeted by IDH2 inhibitors (AG-221). In an updated analysis of a dose-escalation phase I trial, AG-221 was well tolerated and achieved more than 90% inhibition of its target (ie, 2-HG [2-hydroxyglutarate]) in patients with an IDH2 mutation. In 45 evaluable patients with the IDH2 mutation, the overall response rate was 56%; 15 patients achieved a complete response (9 with incomplete platelet recovery), and 10 had a partial response; 17 patients had stable disease throughout the treatment period. Moreover, responses were durable, lasting as long as 9 months on study. No patient in complete remission has relapsed.

 

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ASCO University
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 23, 2015 8:58 AM

Patient Case Update

She was enrolled in the phase one AG-221 clinic trial, testing the safety of the novel IDH2 inhibitor in patients with refractory AML. She is currently on cycle 2 and has achieved a significant reduction in the disease burden. Her last marrow demonstrated 5% bone marrow blasts, with 8 metaphases demonstrating t(6;11). There were no circulating blasts.

The overall plan is to achieve a CRI and then proceed with a reduced intensity conditioning matched unrelated donor allogeneic stem cell transplant.

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Eric James Duncavage, MD
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 23, 2015 9:00 AM

Course Faculty Summary

In this case study a woman presents with a painful nodular skin lesions and profound cytopenia and is found to have Sweet’s syndrome and AML with an MLL gene rearrangement.  Important points:

  • Approximately one third of patients with Sweet’s syndrome have an underlying malignancy, especially hematologic malignancies such as AML and myelodysplastic syndromes.  Patients with suspected Sweet’s syndrome should be evaluated for cancer.
  • MLL gene rearrangements are present in 10% of AML and may also be seen in B-lymphoblastsic leukemia/lymphoma.  MLL gene rearrangements generally portend a worse prognosis and may be associated with mixed phenotype leukemias.
  • Cancer gene panels including those used to evaluate leukemia are becoming more commonplace.  These panels allow for sequencing based evaluation of numerous genes and a reduced cost compared to standard methods.  

 

11471

Mrinal M. Patnaik
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 23, 2015 9:02 AM

Course Faculty Summary

This is a 67 year old female who presented with a nodular skin rash and pancytopenia; who was subsequently found to have a MLL-MLLT4 rearranged acute myeloid leukemia.

  • Skin rashes are common in AML and can often precede the diagnosis. The differential diagnosis includes; viral infections (vesicles, exanthems and enanthems) leukemia cutis, sweets syndrome, and necrotizing eccrine hidradenitis.
  • MLL gene rearrangements (11q23) are seen in ~ 10% of all AML cases and portend a poor prognosis.
  • Next generation sequencing, including RNA sequencing studies add important prognostic and therapeutic dimensions to the management of AML.  In this case the patient with refractory AML was found to have an IDH2 mutation which was targeting by an IDH2 inhibitor (AG-221) and has thus far demonstrated a positive response.

11476

ASCO University
Re: Acute Myeloid Leukemia (Sept. 2015): Molecular Oncology Tumor Boards
Sep 23, 2015 9:04 AM

Thank you to Drs. Duncavage and Patnaik 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.

Please check back in mid-October for a new case in this series related to melanoma.   


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