ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board

ASCO University
Jun 13, 2018 9:29 AM

Participant 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 bi-monthly with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. David Porter (Hematologist from Perelman School of Medicine at University of Pennsylvania) and Jennifer Dunlap (Pathologist from Oregon Health & Science University).

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.

Participants 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.

When posting, please abide by the terms and conditions of this website.

Comments

15641

ASCO University
Re: ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board
Jun 13, 2018 9:34 AM

Patient Case #1

Age/Sex: 23 year old male

Medical History: No significant medical history prior to diagnosis of ALL

Type of Tumor: B-lymphoblastic leukemia, BCR-ABL1-like (Ph-like ALL)

Relevant Markers: At diagnosis, cells were CD10, CD19, CD22, CD25, CD34, dim CD45, CD58, TdT, and HLA DR positive.

Karyotype (ISCN Nomenclature): 46 XY [20].

FISH testing is negative for bcr/abl

Profiling shows a Ph-like phenotype.  CRLF2 overexpression.  

PCR testing negative for bcr/abl

Prior Treatment History/Response:
Diagnosed with B-lymphoblastic leukemia, BCR-ABL1-like (Ph-like ALL) in 2015.

  • He was treated on a clinical trial using multi-agent chemotherapy with a “pediatric/young adult regimen”.  
  • After induction, no morphologic evidence of residual B-ALL but minimal residual disease (MRD) testing is positive.
  • An HLA matched sibling is identified
  • Plans are made for consolidation.

At month 3 visit during consolidation a bone marrow evaluation shows a hypercelluar marrow with 60% blasts.

  • Treated with a “hyper-CVAD regimen” for 2 cycles (includes cyclophosphamide, Adriamycin, vincristine, high-dose Decadron, high-dose araC, high-dose methotrexate) without response.
  • Received blinatumomab for 28 days.  
    • Cytoreduction without a complete response.  Day 28 bone marrow evaluation shows 20% blasts.
    • Second cycle without response.
  • Receives inotuzumab.
    • Bone marrow again shows 20% blasts
    • Cytogenetics remain normal

Co-morbidities: None

Images/Scans/Pathology: Bone marrow biopsy at diagnosis shows B-lymphoblastic leukemia involving 90% of a hypercellular marrow (95% marrow cellularity)

15646

ASCO University
Re: ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board
Jun 13, 2018 9:36 AM

Discussion Questions

1.  What treatment options would be considered next?

2.  What are the clinical features and molecular hallmarks of Ph-like ALL?

15661

David Porter
Re: ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board
Jun 18, 2018 9:04 AM

Course Faculty Response - Dr. David Porter

Question 1 response: This patient has refractory ALL. He is incurable with standard chemotherapy.  Several therapies are available to induce remission in patients with chemotherapy refractory disease. This patient has failed the anti-CD19/CD3 bi-specific antibody blinatumomab and the chemotherapy conjugated anti-CD22 antibody inotuzumab.  

The only known curative therapy would be allogeneic stem cell transplantation. It is unknown whether anti-CD19 CAR T cells can result in cure but they will induce a high rate of remission.However, transplant for patients with refractory ALL results in poor outcomes with long-term remission rates of 10–25 percent (Duval M, et al. J Clin Oncol. 2010 Aug 10;28(23):3730-8).  This is also associated with extensive morbidity and mortality.

The use of anti-CD19 CAR T cells can result in remission rates of 80–90 percent. The majority of these remissions will be MRD negative.  In pediatric and young adult patients, tisagenlecleucel has resulted in complete response rates of 81% and 50% 6-month leukemia free survival. Relapses after 6 months or very unusual. (Maude SL, et al. N Engl J Med. 2018 Feb 1;378(5):439-448).

While either transplant or CAR T cells can be considered, CAR T cells appear to have a higher probability of remission induction, leukemia free survival, could serve as a bridge to transplant (though it is unclear whether or not transplant would be necessary in patients who achieve MRD negative remission), and should result in a lower risk of treatment related morbidity and mortality.

15666

Jennifer Dunlap
Re: ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board
Jun 18, 2018 9:41 AM

Course Faculty Response - Dr. Jennifer Dunlap

Question 1 response: CAR-T cell therapy is a consideration in this patient. CAR-T cell therapy is a type of adoptive cell immunotherapy (ACT) in which patient’s own T cells are engineered to express a chimeric antigen receptor (CAR) that is directed against a tumor associated antigen. T cells are removed from a patient and genetically modified to express a CAR, expanded ex vivo, and then infused back into the patient.  

A CAR combines an antigen recognition domain, usually a single chain variable fragment (scFV) of a monoclonal antibody, with intracellular T cell stimulatory (usually CD3-z chain) and costimulatory domains (typically 41bb or CD28) into one single chimeric molecule. Importantly, CAR-T cells are able to bind target antigens independent of major histocompatibility complex (MHC). This increases therapeutic efficiency as many tumors downregulate MHC class I receptors as a means to evade immunosurveillance. CAR-T cells targeting CD19 have demonstrated remarkable clinical success in refractory B cell malignancies and are now FDA approved for the treatment of relapsed or refractory B lymphoblastic leukemia and large B cell lymphomas.

Question 2 response:

BCR-ABL1-like B-ALL (Ph-like ALL) is a subtype of B-lymphoblastic leukemia/lymphoma that shows a gene expression profile similar to that of Philadelphia chromosome-positive (Ph+)  ALL but lacks the BCR-ABL1 fusion.  Ph-like ALL occurs in 10-25% of all patients with B-ALL, with enrichment in children with high risk B-ALL, Down syndrome, Hispanic/Native American patients, adolescents and adults.  Ph-like ALL is associated with inferior clinical outcome and high risk features including older age, increased WBC and increased minimal residual disease (MRD) after induction. Given the clinical implications, BCR-ABL1-like B-ALL was included as a provisional entity in the 2017 Classification of Tumor of Hematopoietic and Lymphoid Tissues.

Ph-like ALL are defined by gene expression profiling but are otherwise genetically heterogeneous and exhibit various genetic alterations that deregulate cytokine receptor signaling and tyrosine kinases.

The majority of these involve alterations that activate JAK/STAT signaling or ABL class fusions. The most common genetic lesions include:  

  1. Alterations that activate JAK/STAT signaling:
    • Rearrangements or point mutations of CRLF2
    • Rearrangements of JAK2 or EPOR
    • Other mutations in JAK-STAT signaling (JAK1/3, IL7R, SH2B3, TYK2, IL2RB and TSLP)  
  2. ABL-class fusions involving ABL1, ABL2, CSF1R, PDGFRA, PDGFRB
    • IKZF1 (IKAROS) mutations
    • RAS pathway mutations (KRAS, NRAS, NF1, PTPN11)
    • Rare kinase alterations involving NTRK3, BLNK, PTK2B, and TYK2 

IKZF1 alterations are detected in 70-80% of Ph-like ALL. Approximately half of Ph-like ALL have rearrangements in CRLF2, and of these, about half have concomitant mutations in JAK1 or JAK2. Rearrangements of JAK2 or EPOR are seen in approximately 7% and 5% of cases, respectively and ABL class fusions are detected in 10%. Importantly, these underlying genomic alterations are potentially targetable. Specifically, kinase inhibitors (imatinib and dasatinib) may be considered in cases with ABL-class fusions and JAK2 inhibitors in cases with alterations that activate JAK/STAT signaling. Clinical trials are currently underway to investigate the efficacy of targeted therapy in Ph-like ALL.

15671

ASCO University
Re: ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board
Jun 18, 2018 9:43 AM

Patient Case Update

The patient has refractory B ALL and residual disease after multiple therapies.  While options included allogeneic SCT with HLA matched brother or CAR T cells, CAR T cells are likely a more effective option at least initially.

Patients who undergo allogeneic stem cell transplantation with refractory disease have a very high risk of relapse. Even patients who are MRD positive at the time of transplant have a much higher risk of relapse in patients who are MRD negative.  Therefore if there is an effective to induce an MRD- state, that would be preferable over transplant.

The patient received CAR-T therapy (tisagenlecleucel).
3 days after the infusion of tisagenlecleucel he has fevers that escalate over the next several days.  On day 6 after T cell infusion his temperature is 104.6, and he has significant nausea, anorexia, myalgias, and headaches.  No other neurologic toxicities are noted.
He is treated with broad-spectrum antibiotics but an exhaustive infectious disease workup fails to identify an infectious source of his symptoms.
Ferritin levels rise from 650 and baseline to 22,000. CRP was 1.5 at baseline and is 18.5.
On day 8 after T cell infusion, he remains febrile (103.4) and is noted to be tachypneic.  His BP is at his baseline of 124/80.  Respiratory rate is 22, oxygen saturation was 86% on room air and exam showed tachycardia (heart rate 110) and diffuse fine rales at both bases.  The CXR showed bilateral increased interstitial markings.  He was place on 2l O2 via nasal canula and given furosemide with good response. However 4 hours later oxygen saturations continue to drop and he is escalated to 50% oxygen supplementation via a face mask. His BP is lower than normal at 90/70.
He then receives tocilizumab.  Over the next 4 hours, his fevers resolve and his BP normalizes.  4 hours after tocilizumab he is on 4 liters of O2 via nasal cannula.  12 hours after tocilizumab he is on 2 liters of O2 via nasal cannula and oxygen supplementation is discontinued 24 hours after tocilizumab is given.    
Over the next several days he remains afebrile and biochemical abnormalities returned to baseline.
28 days after T cell infusion bone marrow morphology is normal. Cytogenetics are normal and MRD testing is negative.

15676

ASCO University
Re: ALL and Cellular Therapy (June 2018): Molecular Oncology Tumor Board
Jun 18, 2018 3:33 PM

Discussion Questions

1. What was the cause of the patient’s fevers, clinical symptoms after CAR T cells and biochemical abnormalities?

2. Should this patient now undergo allogeneic SCT?

3. What additional testing would help determine the next best therapy?


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