Acute Lymphoblastic Leukemia (B-cell) Flashcards
immunophenotypic categories of ALL
B-precursor ALL
B-precursor with myeloid features
Mature B cell
T-cell
signs/symptoms
painless lymphadenopathy, HSM, painless testicular swelling, constitutional symptoms (fever, fatigue), bruising/bleeding, leukostasis, TLS, mediastinal mass, MSK pain
Variables predicting clinical course of ALL
age, immunophenotype, WBC count, genetic aberrations, CNS involvement, response to therapy
General treatment approach of patients less than 70 without major comorbidities who are Ph+
induction chemo + TKI’s –> If Cr is achieved, pt undergoes ASCT in first remission followed by consideration for use of maintenance TKI for period of time following allogeneic transplant
Treatment for ALL in general
Combination chemotherapy
hyper-CVAD regimen
cyclophosphamide, vincristine, doxorubicin (also known by its trade name, Adriamycin), and dexamethasone.
General treatment strategy for PH + ALL
Induction with multiagent chemotherapy -and TKI –> once first CR achieved, find HLA matched sibling –> consolidation with allogeneic stem cell transplant
Treatment in general for PH+
Multi agent chemotherapy and a BCR/ABL TKI
Major branch point in ALL
Presence of philadelphia chromosome (Philadelphia negative or positive ALL)
Why is leucovorin given with MTX?
Chemoprotectant – since MTX depletes folic acid in cells, it also targets non-cancerous cells, so leucovorin (reduced folinic acid) is added as a rescue agent 24 hours after methotrexate is given
Why do you need to draw MTX levels on a regular basis?
At a specified level, it is safe to stop leucovorin administration
WBC count in b-cell ALL
Anything – May be decreased, normal, or very high
Clinical course
Variable – can be indolent or aggressive
Diagnosis in general
- Detection of lymphoblasts with characteristic immunophenotype by flow cytometry/IHC
Essential characteristic of B-ALL on flow cytometry
Expression of B cell antigens + absence of T cell antigens
What is an immunophenotype?
Antigens or markers expressed on cell surface
Characteristic b cell antigens
CD19, 22, 79
Prognostic importance of philadelphia chromosome?
Used to be considered bad, but don’t really know now that TKI’s are available
Term for quantifying remaining burden of leukemia cells after induction therapy
MRD – measurable or minimal residual disease)
Preferred induction therapy regimen
No agreed upon standard, center specific. None have been directly compared in prospective RCTs.
Most chemo regimens for ALL contain….
Vincristine
steroid
anthracycline
*rituxan if CD20 positive
Prognosis
- Most achieve CR after induction chemo
Definition of CR in ALL
Less than 5% blasts from bone marrow and blood + restoration of normal hematopoiesis
Better marker for prognosis than CR
MRD
Resistant disease defined as
Inability to achieve a CR with initial induction therapy
Workup prior to diagnosis
- Flow cytometry looking for cell markers of precursor B-cell
- Cytogenetics
- PCR for BCR-ABL
- NGS
Demographic incidence
bimodal (young patients and older than 45)
B-cell subcategories in ALL
Ph-positive, Ph-like, Ph-negative
Therapy is based on
1) cytogenetics (Ph+ or Ph like, hypodiploidy, KMT2A-rearrangements) (There are different strategies based on cytogenetics –TKIs only, intensive chemo then transplant)
2) Age (Older than 60, younger than 40)
Management of older patient with ALL
Lower intensity chemo
Assessment of Minimal residual disease for PH+
PCR for BCR-ABL1
What is Ph-like ALL?
Similar gene expression to those of Ph+ ALL but with no BCR-ABL
Concept of Minimal residual disease
- Depth of remission is highly correlated to prognosis . Trumps all other prognostic factors.
- In patients who achieve MRD, HSCT does not impact outcome.
Agent approved for MRD-positive B-cell ALL
Blinatumomab
Severe hypodiploid is associated with what
TP53 mutation
Regimens used for young adults in general
Pediatric chemo regimens
commonly used ALL regimens
1) CALGB (Linker, Larson, ABC regimen) – asparaginase containing
2) Hyper CVAD
Hyper CVAD is
cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) ***alternating with high-dose methotrexate and high-dose cytarabine
- This regimen includes a risk-stratified schedule of central nervous system prophylaxis with intrathecal methotrexate and intrathecal cytarabine.
Who is transplanted in ALL?
- *Patients with highest relapse risk
1) Ph+ ALL
2) MLL (all translocations though t(4:11) the worst
3) Hypodiploid
4) ETP (early T-cell ALL) - But you have to consider whether MRD negativity trumps decision to transplant
Relapsed/refractory ALL management options
- Transplant
- Blinatumomab, inotuzomab
- CAR T-Cell (unknown role at this point)
Blinatumomab mechanism
BiTE antibody designed against direct cytotoxic T-cells to CD-3 and CD-19 expressing cancer cells
Induction regimen for most PH negative ALL patients
HYPER-CVAD
Consolidation management for most ALL patients
Allo transplant
Blinatumomab administration
- 24 hr infusion for weeks in a row (at least 6 cycles, have to be inpatient for first 9 days of treatment)
Blinatumomab side effects to know
1) CRS
2) Neurotoxicity
Major issue for ALL induction therapy
- regimens are highly myelosuppressive, which is why hospitalization is required for blood product support
Important complication of asparaginase therapy to be mindful of + why
Venous thrombosis (reduces ATIII, protein C and S)
class of drug etoposide is in
epipodophyllotoxins
what is restoration of normal hematopoieisis defined as?
25 percent cellularity and normal peripheral blood counts
What are the high risk ALL subtypes?
1) Ph-like and Ph-positive
2) CNS involvement
3) Burkitt-type
ALL and CNS involvement
- ALL has a high risk of CNS involvement, thus all current treatment regimens include CNS prophylaxis
Management of CNS involvement with ALL
- whole brain cranial irradiation + at least 6 doses of intrathecal MTX
Management of Ph-like
- should be considered for early allo transplant
Preferred TKI for PH+ ALL
None, choice depends on toxicity profile, comorbidities, and availability (no head to head studies)
Preferred TKI per UTD for PH+ ALL
Dasatinib (data, some CNS penetration, well-tolerated)
TKI duration
TKIs are continued through post-remission management
Why imatinib is not used
less effective than second and third generation TKIs
CALGB regimen
begins with a cycle of dasatinib plus dexamethasone, followed by systemic and intrathecal methotrexate, and for patients with >20 percent lymphoblasts in bone marrow, vincristine and daunorubicin.
Prognostic significance of TEL-AML1
good risk
Patients with ALL who require CNS prophylaxis
ALL patients
medications used for CNS prophylaxis with ALL
- methotrexate
- cytarabine
clinical significance of CD20 expression in Ph negative ALL
- adverse prognosis
High risk features in ALL
1) poor cytogenetics
2) elevated white count greater than 30K for B cell or greater than 100K for T cell
basic HyperCVAD regimen
CVAD alternating with HD-MTX + cytarabine
AYA means
adolescent and young adult
Induction therapy for PH+ ALL under age 65
TKI + vincristine + dex TKI + multiagent chemo TKI + steroid TKI + multiagent chemo CALGB blinatumomab + TKI
Duration of TKI in maintenance phase
At least 1 year
Consolidation therapy for PH+ in CR
Continue TKI + allotransplant if donor available (in TKI era, still unclear if transplant is needed)
IF donor not available → continue multiagent chemo +TKI
BCR-ABL1 transcripts that can be seen in PH+ ALL
BOTH p190 and p210
PH+ B-ALL markers
TdT + Cd25
Adverse risk features in ALL
- hypodiploidy
- KMT2A
- t(v;14q23)/IgH
- complex karytoype
- Ph-like
Unique feature of management of patients under 21
- IF they achieve MRD negativity, allo-transplant may not confer any advantage over chemo + TKI, they are not taken to transplant
Most common toxicities of asparaginase
- pancreatic (pancreatitis) + hepatic
Medication used to treat allergic reactions to pegasparaginase
- Erwinia chrysanthem
Best regimen for frail adults
TKI + steroid
Preferred TKI for hyper-CVAD
ponatinib
Targeted therapies for anti-CD22
- inotuzumab + blinatumomab
blinatumomab mechanism
- anti-CD22 immunoconjugate
inotuzumab mechanism
- carries a chemotoxin called calicheamicin (upon internalization, binds to DNA which induces a double-strand DNA break, leading to apoptosis)
Blincyto SE’s
- hypotension
- cytokine release syndrome
- encephalopathy
- edema
Tisangenlecleucel indication
Patients under age 26 with refractory ALL or greater than 2 relapses
Refractory or relapse options
- Blinatumomab
- Allo-HSCT
- CAR-T cell (kymriah + brexu-cel)
- inotuzumab (ADC)
Management of ALL patient with isolated extramedullary relapse (testicles or CNS)
- systemic therapy (prevent bone marrow relapse)
lab results of Ph like
- Philadelphia chromosome negative on cytogenetics
- ABLclass rearrangements (ABL1, ABL2, PDGFRA, PDGFRB, FGFR) on molecular analysis
most frequently employed method for MRD assessment
- flow cytometry (specific assays are designed to detect abnormal MRD immunophenotypes), PCR, and NGS
basic concept of MRD
- presence of leukemic cells below the threshold of detection by conventional morphologic methods
optimal sample for MRD
initial pull of bone marrow aspirate
management of Ph negative patient is in CR1 but MRD+
blinatumomab then transplant (eliminate MRD prior to transplant)
Sanctuary sites for leukemic cells
CNS + testes (leukemic cells are protected relatively from chemotherapeutic agents)
What is the CALGB regimen?
Daunorubicin, vincristine, prednisone, pegaspargase
What is AYA cancer population defined as
Ages 15-39
Management of AYA ALL population
- pediatric regimens (CALGB)
second line therapy for ALL typically
etoposide/ifosfamide/mitoxantrone
Side effect to know about with inotuzumab
- severe liver damage (veno-occlusive liver disease)
Percentage of hemosiderin laden macrophages among all alveolar macrophages on iron staining from BAL required for DAH diagnosis
greater than 20%
management of Ph+ ALL patient on TKI with rising BCR-ABL oncoprotein
- ABL1 kinase domain mutation testing (same as for CML patients)
First line asparaginase drugs
- pegaspargase
- calaspargase
- NOT asparaginase erwinia chrysanthemi (second line)
high-risk features of ALL
poor cytogenetic features of WBC>30k
MRD+ threshold
greater than 0.01%
HyperCVAD part A? Part B?
part A is cyclophosphamide, vincristine, doxorubicin, part B is MTX, cytarabine
What is triple IT?
steroid + MTX + cytarabine
White count denoting high risk ALL
50K
Management of young, fit person who has PH+ w/ ALL
Rituximab and hyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone) alternating with high dose methotrexate and cytarabine plus CNS prophylaxis and tyrosine kinase inhibitor
PH negative ALL management in older adults with good performance status
Inotuzumab ozogamicin + mini-hyper-CVD
relapsed refractory options
Blinatumomab (blincyto)
If young → CAR-T (kymriah + brexu-cel) then allo-HSCT
IF CD22+ → inotuzumab
Allo-HSCT
How is LBL treated
Essentially the same as ALL and not like most other aggressive lymphomas
What is lymphoblastic lymphoma (LBL)?
Extramedullary blast proliferation +/- up to 20% blasts in the bone marrow
Most common “PH like” gene rearrangement in ALL patients
CRLF2
