Acute, Chronic, Pediatric Leukemias- Heemer

There are 2 types of acute, and 2 types of chronic leukemias. What are they?

Acute: Acute Myeloid Leukemia, Acute Lymphoid Leukemia

Chronic: Chronic Myeloid Leukemia, Chronic Lymphoid Leukemia

Leukemia is the leading cause of cancer-related deaths in what patient population?

in pts. <20

Although the exact cause of acute leukemias is unknown, what are some factors that are associated?

• genetics

• environmental

• socioeconomic

• toxins

• immunologic status

• viral expsoures

Leukemic cells have growth and/or survival advantages over _________ cells.

normal

ALL is classified based on whether ____ or ____ are effected?

B or T cells

Leukemias are associated with chromosome alterations and structural abnormalities. What is the MOST COMMON translocation in adult ALL?

• t(9:22) or Philadelphia chromosome

  • known as Ph+

• causes fusion of BCR signaling protein to the ABL

What are the general and common signs and symptoms of acute leukemias?

(i don’t think that important)

• general- very vague!! tiredness, lack of exercise, weight loss, feeling unwell

• common- pallor, malaise, palpitations, fatigue, bruising, fever

What blood disorder is common in 28% of ALL and 50% of AML?

thrombocytopenia

What electrolytes may be elevated in Acute leukemias?

potassium and phosphate

What are the 5-6 phases of treatment for childhood ALL?

1. induction

2. consolidation therapy

3. interim maintenance

4. delayed intensification

5. interim maintenance II (high risk only)

6. maintenance therapy

What is a MANDATORY component of ALL treatment regimens?

CNS prophylaxis

What is the goal and four-drug regimen for the INDUCTION phase of childhood ALL treatment?

• goal—> quickly induce complete response

• 4 drug regimen: vincristine + glucocorticoid + pegaspargase + daunorubicin (can be any anthracycline)

What is the goal and treatment options for CNS prophylaxis in ALL treatment?

• goal—> get rid of leukemic cells from CNS

• can use:

  • IT or IV methotrexate and cytarabine (both, or one or the other)

  • cranial irradiation

  • dexamethasone

What is consolidation therapy in terms of ALL? What is the goal? What drugs are used?

• consolidation therapy is after CR from induction therapy

• goal: eliminate any leukemic cells remaining after induction therapy

• drugs: vincristine, 6-MP, IT methotrexate

  • others can be added if high risk

In ALL, Interim Maintenance and Delayed intensification can be combined and called “reinduction”. What is this used for and what are the normal drugs?

• used to maintain remission or decrease cumulative toxicity

• drugs: IV or oral methotrexate and vincristine, oral 6-MP

What drugs are usually part of maintenance therapy for ALL treatment?

6-MP daily or methotrexate weekly

SUMMARY OF ALL TREATMENT IN CHILDREN:

1. induction—> goal is to induce complete response

   • drugs: 4 drug regimen (vincristine, steroid, pegaspargase, daunorubicin)

     • add imatinib if Ph+

2. consolidation therapy—> after complete response

   • drugs: vincristine, 6-MP, IT methotrexate

3. interim maintenance- “reinduction”—> maintains remission/decrease toxicity

   • drugs: IV or high-dose methotrexate and vincristine or 6-MP

4. delayed intensification- “reinduction”- refer to #3

5. interim maintenance II

6. maintenance therapy

   • drugs: daily 6-MP, weekly MTX

Additionally: must do CNS prophylaxis to get rid of leukemia cells in the brain. drugs: IT or IV methotrexate and/or cytrabine, cranial irradiation, dexamethasone

For ALL treatment what is added to the 4 drug regimen is you are Ph+?

imatinib

The treatment for pediatric ALL is similar, but not the same as adult ALL. What is the most common 4 drug regimen used in ADULT ALL?

vincristine + steroid + asparaginase + anthracycline

(difference from pediatric is asparaginase) (for reference pediatric is vincristine, steroid, pegaspargase, daunorubicin/anthracycline)

In adults, what can you use in addition to the 4-drug regimen for ALL the following:

• targeting Ph+

• CD20 targeting

• stem cell targeting

• Imatinib, Dasatinib

• Rituximab, Ofatumumab

• Hematopoietic stem cell transplantation

For ALL treatment in adults, what drugs can be used for relapsed disease? Describe them.

• clofarabine- purine antimetabolite

• nelarabine- purine nucleoside analogue

• blinatumomab- BiTE

• Inotuzumab- targets CD22

• Tisagenlecleucel- CD19 T-cell therapy

What are the 2 treatment phases of AML treatment?

• induction

• post-remission therapy

What is the standard induction regimen for AML treatment? What is the regimen called?

• daunorubicin + cytarabine

• regimen is called “7+3”

  • cytarabine for 1-7days

  • daunorubicin 1-3 days

What is added to the 7+3 induction regimen for AML treatment if you are <60YO w/ intermediate-risk disease cytogenetics with FLT3-mutations?

midostaurin (for FLT3 mutations)

What are options for AML tx if you are >60YO and are not candidates for intensive remission induction? (idk how important)

• Venetoclax (BCL-2 inhibitor)

• Enasidenib

• Gemtuzumab

• Glasdegib

• Ivosidenib

“VEGGI”

What can be used for post remission therapy for AML treatment?

(idk how important)

• cytarabine

• midostaurin (if FLT3 positive)

• gemtuzumab + daunorubicin + cytarabine

• allogeneic HSCT

• autologous HSCT

Acute Promyelocytic Leukemia is an AML subtype. What is the cytogenetic marker? What does the treatment include?

• t (15;17)

• tx: tretinoin

BIG PICTURE IDEAS FROM ACUTE LEUKEMIA LECTURE:

• Acute Leukemias

  • leading cause of cancer-related deaths in <20

• ALL

  • philly chromosome in 25% of pts.

  • must do CNS prophylaxis for all tx regimens

  • 5-6 phases childhood tx

    • 4 DRUG REGIMEN FOR INDUCTION

    • maintenance therapy

  • Imatinib if Ph+

  • adult regimen—> slightly different then childhood

• AML

  • standard induction regimen “7+3”

  • add Midostaurin for FLT3 mutations

What is CML? How does it initially present?

• it is a myeloproliferative disease

  • pluripotent hematopoietic stem cells—> turn cancerous

• initial presentation:

  • bone marrow hyperplasia

  • accumulation of differentiated myeloid cells in peripheral blood

What are the risk factors for CML? What aren’t?

• risk factors: ionizing radiation

• NOT ASSOCIATED WITH:

  • hereditary- lowkey unique

  • familial

  • geographic

  • ethic

  • economic status

95% of patients with CML have what gene mutation?

• philly chromosome aka the BCR-ABL fusion gene

What are the clinical phases of CML?

• chronic phase (CP)

• advanced phase (AP)

What algorithm uses prognostic factors for patients in the CP (Chronic Phase) of CML?

• sokal algorithm

What is the only proven therapy to eradicate malignant clones from bone marrow in CML?

allogeneic hematopoietic stem cell transplantation (HSCT)

When is conventional chemotherapy utilized in CML tx?

to temporarily control WBC counts

What class of drugs has revolutionized treatment of CML and is used for initial tx now?

TKIs (now pts. can live/control disease longer)

What are 3 TKIs that can be used for Ph+ CML tx?

• Imatinib - 1st line

• Dasatinib

• Nilotinib

Imatinib has CYP interactions with what?

CYP3A4, 2C9, 2D6

(p.s. from kearns—> she says also CYP450)

Assess for underlying _____________ disease before starting dasatinib.

cardiopulmonary disease

For Nilotinib and Imatinib and ADR is _______________.

hepatotoxicity

CLL is the______ common form of leukemia in the U.S.

most

What are the risk factors for CLL?

• male

• white

• family

• advanced age

What is the pathophysiology behind CLL? What does cancer do to normal B-cells?

• CLL makes a “neoplastic clone of CD5 cells”

  • aka in this leukemia B cells are cloned and these cancerous B cells than express lots of CD5 which makes them evade apoptosis

4%-10% of CLL undergo a transformation called ___________________.

Richter’s Syndrome

What are the 2 common staging systems used for CLL? Describe the one used in the U.S.

• Rai- staging system combined into risk classification (low, inter.,high)

• Binet

What is an important predictor of survival outcomes in CLL?

immunoglobulin heavy-chain variable (IGHV) gene mutation status

• if IGHV unmutated= poor prognosis

What are some biomarkers associated with CLL?

• CD38 expression

  • shorter survival/early progression

• Z-associated protein 70 (ZAP-70)

  • rapid progression

What drug classes can be used in the tx of CLL?

• alkylating agents- declining use

• purine analogs

• Anti-CD20 MAbs

• Alemtuzumab

• BTK inhibitors

• PI3K inhibitors

• Venetoclax

What purine analogs are used in CLL tx?

• Fludarabine

• Cladribine

• Pentostatin

What anti-CD20 mAbs are used in CLL therapy?

• Rituximab

• Obinutuzumab

• Ofatumumab

Alemtuzumab targets what CD?

CD52 on B and T cells

What drugs are PI3K inhibitors used in CLL tx?

• Idelalisib

• Duvelisib

What are the boxed warnings of PI3K inhibitors? What do they require?

• BBW—> hepatotoxicity, diarrhea, colitis, pneumonitis

• requires—> pneumocystis jiroveci pneumonia prophylaxis and monitoring for CMV reactivation

________ plays a key role in B cell survival, proliferation, adhesion, and cell migration. Introduction of these inhibitors have radically changed treatment of CLL.

Bruton’s tyrosine kinase (BTK)

What drugs are BTK inhibitors? What generation are they?

• Ibrutinib- 1st gen

• Acalabrutinib- 2nd gen

• Zanubrutinib- 2nd gen

Ibrutinib has what drug interactions? What is the main warning?

CYP3A4, hemorrhage

What are the 1st line tx options for CLL pts. with del 17p and without del 17p?

• with del 17p- Ibrutinib, Acalabrutinib ± Obinutuzumab, venetoclax + obinutuzumab or Zanubrutinib

• without del 17p or TP53 mutation- Ibrutinib, Acalabrutinib ± Obinutuzumab, venetoclax + obinutuzumab

(only difference is whether you can use Zanubrutinib)

What is most common pediatric malignancy?

ALL

Among pediatric patients, what might be the only presenting symptoms?

pain in the extremities or joints

Diagnosis of ALL in children generally requires demonstration of ____% or greater bone marrow lymphoblasts.

20%

Immunophenotypic classification of ALL involves what test to determine the presence of cell surface antigens on lymphocytes?

flow cytometry

ALL in children is broadly classified into what 2 groups? Which is more common?

• B-cell ALL- more common

• T-cell ALL

Genetics abnormalities in B-cell Pediatric ALL can include:

• hyperdiploidy

• hypodiploidy

• rearrangements

Genetics abnormalities in T-cell Pediatric ALL can include:

• mutation NOTCH1

• rearrangements in TFs TLX1, TLX3, LYL1, TAL1, KMT2A

disclaimer: for the pediatric leukemia lecture she describes the same tx as in the acute leukemia lecture for ALL so refer to the cards about that heavily!!!!

know the phases, CNS prophylaxis, etc.

PRACTICE:

Match the goal with the phase of treatment:

Phase	Goal
	eradicate any remaining cancerous cells after induction therapy
	prevent disease relapse
	induce a complete response

Phase options: induction, maintenance, consolidation

Phase	Goal
consolidation	eradicate any remaining cancerous cells after induction therapy
maintenance	prevent disease relapse
induction	induce a complete response

What is the consolidation phase of pediatric ALL most affected by?

• risk stratification

  • lower risk= less intense therapy

  • higher risk= more intense therapy

How long does the maintenance phase of pediatric ALL last?

2-3 yrs

Dosing of 6-MP for the maintenance phase of pediatric ALL depends on the pharmacogenomics of what?

• TPMT phenotype

• NUDT15 phenotype

What is the dosing for 6-MP for maintenance therapy of pediatric ALL for the following TPMT phenotypes:

• homozygous for normal fxn

• heterozygous for no fxn allele

• homozygous for no fxn allele

• homozygous for normal fxn- regular dose

• heterozygous for no fxn allele- start at 30-80% of full dose

• homozygous for no fxn allele- start at ~10% of full dose

What is the dosing for 6-MP for maintenance therapy of pediatric ALL for the following NUDT15 phenotypes:

• homozygous for normal fxn

• heterozygous for no fxn allele

• homozygous for no fxn allele

• homozygous for normal fxn- regular dose

• heterozygous for no fxn allele- start at 30-80% of full dose

• homozygous for no fxn allele- start at 10 mg/m²/day