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Which cells do myeloid stem cells differentiate into?
erythrocytes, platelets, monocytes, basophils, neutrophils, eosinophils
Which cells do lymphoid stem cells differentiate into?
T- lymphocytes and B-lymphocytes
What are blast cells? How many does the bone marrow normally have?
- Intermediate cell types that develop from stem cells but have not fully matured yet into erythrocytes, lymphocytes, etc.
- Normal is less than 5% blasts
Define acute leukemia
presence of at least 20% leukemic blasts in the bone marrow or blood
How are leukemias classified?
By disease acuity and cell of origin
Genetic alterations leading to the formation of leukemic blasts
- Oncogene activation leading to increased proliferation
- Loss of signals for differentiation
- Loss of tumor suppressor genes
- Loss of apoptosis signals
Why are acute leukemias an emergent situation?
they're rapidly progressive and can lead to death within weeks to months without treatment
Why are leukemic blasts a problem/what do they do? (pathophys)
They fail to differentiate and rapidly proliferate eventually crowding out stem cells in the bone marrow. Normal hematopoesis is impaired leading to anemia, neutropenia, and thrombocytopenia. Over time the leukemic blasts may migrate out of bone marrow and infiltrate a variety of tissues (blood, spleen, lymph nodes)
CNS and testes may serve as sanctuary sites in which type of leukemia?
- (CNS involvement also possible with AML - M4 and M5 subtypes)
What population does AML usually affect?
Clinical presentation of AML
- leukopenia/leukocytosis - fever, infections
- incr K and PO4
- bone pain
- Auer rods
- gum hypertrophy (M4, M5)
- infiltration of gingivae, skin, soft tissues, or meninges (M4, M5)
Is radiation more useful in leukemia or lymphoma?
lymphoma - very limited use in leukemia
How soon is chemotherapy usually started in pts with AML?
promptly after diagnosis - within 72 hours
Which AML patients respond better to chemo usually?
pts < 60 y.o.
What is the induction therapy for AML in pts < 60 y.o.?
- 7+3: cytarabine continuous infusion standard dosing for 7 d + anthracycline (daunorubicin or idarubicin) for 3 d
- HiDAC: High-dose cytarabine + anthracycline (dauno or ida) for 3 d
What is the induction therapy for AML pts > 60 y.o.?
- 7+3 (with a 3rd anthracycline option being mitoxantrone)
- Low intensity therapy: SubQ cytarabine, 5-azacytidine, decitabine
- Intermediate intensity therapy: clofarabine
- Best supportive care: hydroxyurea, transfusions
SEs of cytarabine
- High dose: cerebellar tox (slurred speech, mystagmus, dysmetria); conjunctivitis/keratitis
SEs of anthracyclines
- cardiac toxicity
- urine discoloration
Supportive care for AML
- For myelosuppression: RBC transfusion for anemia if Hgb < 8 or any sx, Platelet transfusion for thrombocytopenia if plt count < 10,000 or signs of bleeding, Myeloid growth factors for leukopenia - consider after chemo, monitor CBC with diff and platelets daily
- For TLS: allopurinol, rasburicase, hydration. Monitor lytes, BUN, Scr, uric acid, PO4
- For infx: Antifungals (fluconazole), Antivirals (acyclovir to prevent HSV reactivation), Antibiotics (SMX/TMP to prevent PCP). Monitor vitals esp temp
- For cerebellar tox (only with HiDAC): neurologic assessments, monitor renal fxn, d/c if tox develops
- For conjunctivitis/keratitis (only with HiDAC): saline or steroid eye drops (start with chemo and continue for 24 h after)
- Antiemetics, good oral care, dosing, drug intx
With AML, how is it determined if CNS therapy for CNS leukemia is needed? What is the treatment?
- CNS leukemia - M4 and M5 subtypes; WBC > 100,000 at diagnosis
- if CT/MRI or LP is (+), give CNS therapy
- CNS therapy = intrathecal chemotherapy with methotrexate +/- cytarabine biw until clear then weekly x 4-6 weeks. Start concurrently with induction therapy unless on HiDAC in which case begin after induction tx is complete.
What subtype of AML is APL?
What is the most curable of all AML subtypes?
M3 - APL
What population does APL primarily affect?
- younger patients (diagnosis typically betw 15 -60 yo)
- risk factors - younger age, hispanic origin, obesity
What mutation is seen in 95-100% of APL cases?
PML-RAR fusion protein
What is the main distinguishing clinical feature of APL?
- severe coagulopathy characterized by DIC
- however, pt is at risk of bleeding b/c all clotting factors are used up
What is the induction therapy for APL?
- ATRA + anthracycline (dauno or ida) +/- cytarabine
- ATRA + As2O3
ATRA side effects
- HA, skin and mucous membrane rxns, bone pain, nausea
- APL differentiation syndrome (aka retinoic acid syndrome)(fever, rapidly rising WBC > 10,000, SOB, hypoxemia, fluid retention, weight gain, pulmonary infiltrates, pleural/pericardial effusions)
Which TKI causes QT prolongation?
What are the SEs of arsenic trioxide?
- QT prolongation
- APL differentiation syndrome
- peripheral neuropathy
- weight gain
What is the supportive care for APL?
- For coagulopathy and overt bleeding: platelet transfusions, fibrinogen with cryoprecipitate and fresh frozen plasma. Monitor platelets, fibrinogen, PT and aPTT.
- For APL differentiation syndrome: Dexamethasone prophylaxis if WBC > 10,000 or treatment if sx. Monitor volume overload and fluid status.
- For QT prolongation: get baseline EKG, avoid other QT prolonging agts (FQs, macrolides, venlafaxine), monitor lytes and creatinine
What supportive care that is common in leukemia is NOT recommended for use in APL?
myeloid growth factors
What population is primarily affected with ALL?
bimodal distribution - kids under 10 and adults over 50
Which ALL patients have a better prognosis?
- kids way more than adults
- can treat pediatric ALL more aggressively than adult
- adults have comorbid conditions, have more drug resistance, have poorer tolerance of treatment and poorer compliance
- adults often Ph+ which has a very poor prognosis
Clinical presentation of ALL
- Leukopenia or leukocytosis
- Incr K and PO4
- Decr Ca++
- testicular enlargement
- chloromas (small, blue-green collections of leukemia cells under the skin)
What is the induction treatment for ALL?
- Any combo of:
- CNS prophylaxis is required:
- intrathecal methotrexate and/or cytarabine
- intrathecal triple therapy with hydrocortisone
- high-dose systemic chemo (MTX or cytarabine)
- draniospinal irradiation
If Ph+, include a TKI
if T-cell ALL, use nelarabine as part of initial tx
Which drug used in induction therapy for ALL is fatal if given IT?
- bleding or thrombosis
- acute anaphylaxis
- severe pancreatitis
- Myelosuppression, n/v, secondary leukemias, sterility, infertility
- Hemorrhagic cystitis - use MESNA
Supportive care for ALL
- For myelosuppression: Anemia - RBC transfusion if Hgb < 8 or sx of anemia; Thrombocytopenia - platelet transfusion if plt < 10,000 or signs of bleeding; Leukopenia - initiate myeloid growth factors after induction therapy. Monitor CBC with diff, platelets.
- For TLS: allopurinol, rasburicase, hydration. Monitor lytes, BUN, Scr, uric acid, PO4.
- For infection: Antivirals (acyclovir for prevention of HSV reactivation); Antibiotics (SMX/TMP to prevent PCP). Monitor vitals esp temp.
- When using high dose MTX: must use leukovorin and monitor pharmacokinetics. Alkalinize urine with sodium bicarb to prevent ppt in kidneys.
- with Cyclophosphamide: use MESNA to prevent hemorrhagic cystitis.
What patient population is usually affected by CML?
What mutation is usually associated with CML?
- the Philadelphia chromosome (Ph)
- BCR-ABL - abnormal fusion protein
- (can also be seen in adults with ALL and rarely in AML)
What does the BCR-ABL abnormal fusion protein do?
encodes for mutant tyrosine kinase which leads to uncontrolled cell proliferation, inhib of apoptosis, accumulation of malignant cells
Describe the clinical course of CML
it is indolent and triphasic
- Chronic Phase: < 10% blasts, asymptomatic, survival several years, treatment responsive
- Accelerated Phase: 10-29% blasts, subclinical presentation, survival 1-2 years, less responsive to tx over time
- Blast Phase: > 30% blasts, presentation similar to AML/ALL, survival 3-10 months, poor response/refractory to tx
Clinical presentation of CML
- thrombocytosis (incr platelets)basophiliahyperuricemia
- incr LDH and B12
- night sweats
- LUQ/abdominal pain
- blood hyperviscosity (retinal hemorrhage, priapism, CVA, tinnitus)
- Chronic Phase: imatinib, dasatinib, or nilotinib
- Accelerated Phase: dasatinib or nilotinib
- Blast Phase: AML or ALL induction tx + TKI or TKI alone
How do we deal with imatinib resistance in CML?
- Primary resistance (lack of efficacy) - switch to nilotinib or dasatinib
- Secondary resistance (loss of efficacy over time) - increase imatinib dose to overcome the resistance
Supportive care for CML
- For Myelosuppression: for neutropenia, hold drug until ANC>/= 1000-1500 then resume or reduce dose, myeloid growth factors; for thrombocytopenia, hold drug until plt >/= 50,000-75,000 then resume or reduce dose; for anemia, RBC transfusions
- For diarrhea: supportive care
- For GI upset (n/v): take with meal and large glass of H2O, divide dose
- For Rash: topical/systemic steroids, dose reduction, interruption or d/c
- With nilotinib - watch out for QT prolongation
Drug intx with meds used to treat CML
- CYP 3A4 inducers and inhibitors
- H2 blockers, PPIs (dasatinib) - needs acid for abs
- Food (nilotinib) - for incr bioavail - take on empty stomach
- QT prolonging agents (nilotinib)
A lymphocytic malignancy involving the lymphoid tissues is called __________. A lymphocytic malignancy involving the bone marrow/blood is called ___________.
- lymphocytic leukemia
Lymphomas commonly present as what kind of tumor?
What are the 2 classifications of lymphoma?
- Hodgkin's lymphoma
- Non-Hodgkin's lymphoma
What symptoms are the hallmark of lymphomas?
B symptoms: fever (T. 100.4), drenching night sweats, and weight loss (> 10% of body weight)
What population is usually affected by Hodgkin's lymphoma?
bimodal distribution - 15-30 and >55
2 classifications of Hodgkin's Lymphoma and what determines this
- 1. Classical HL (95%) - presence of Reed-Sternberg cells
- 2. Lymphocyte-Predominant HL (5%) - lack of Reed-Sternberg cells
Clinical presentation of Hodgkin's Lymphoma
- lymphadenopathy (usually painless - rubbery mass)
- Systemic B symptoms
- chronic pruritis
- extranodal involvement (spleen, lungs, liver, bone marrow)
Treatment of Classical Hodgkin's Lymphoma
- Early-stage disease - radiation in combo with chemo
- Advanced-stage disease - intensive combo chemo
- ABVD: (doxorubicin, bleomycin, vinblastine, dacarbazine)
- Stanford V: (doxorubicin, bleomycin, vinblastine, vincristine, mechlorethamine, etoposide, prednisone)
- BEACOPP: reserved for high risk or unfavorable disease because very toxic and may cause secondary cancers long term
- MOPP: obsolete
What population does Non-Hodgkin's Lymphoma generally affect?
any age, but primarily seen in elderly
3 types of chromosomal translocations in Non-Hodgkin's Lymphoma
- Burkitt's lymphoma
- follicular B cell lymphoma
- mantle cell lymphoma
What population does CLL usually affect?
This is a lymphoproliferative disorder characterized by the accumulation of non-functional B-cells with bone marrow/blood involvement
- (if the involvement is nodal instead of marrow/blood, it is SLL)
Clinical presentation of CLL
- often asymptomatic in early disease
- B symptoms (fever, weight loss, night sweats)
- frequent infx
- autoimmune disease
- secondary malignancy
- Richter transformation (goes from indolent to aggressive form)
Treatment of CLL
- Asymptomatic early-stage disease: observation adn supportive care measures
- Symptomatic or high-risk disease: combo of cyclophosphamide, fludarabine, and rituximab is most common. Also used - chlorambucil, bendamustine, cladribine, pentostatin, alemtuzumab
Supportive care for CLL
- Blood product support
- TLS (allopurinol, rasburicase, hydration)
- Autoimmune cytopenias: if pt has autoimmune hemolytic anemia with fludarabine, stop, treat, and avoid future fludarabine; Immune thrombocytopenia purpura; pure RBC aplasia; Treatment = corticosteroids, rituximab, IVIG, cyclosporine, splenectomy, eltrombopag, romiplostim
- Infections (prophylaxis recommended for pts receiving pruine analogs or alemtuzumab): bactrim to prevent PCP, acyclovir to prevent hepes and varicella reactivation, ganciclovir to prevent CMV reactivation with alemtuzumab
- Vaccination: annual flu, pneumovax q5y, avoid live vaccines
What type of lymphoma is follicular lymphoma?
Likely prognosis with follicular lymphoma
- it is indolent and relatively benign, so relatively long survival
- responsive to tx, but pts are rarely cured
Clinical presentation of follicular lymphoma
- painless lymphadenopathy
- bone marrow involvement
- usually no B symptoms
Treatment of follicular lymphoma
- Chemo +/- Radiation
- rituximab-based regimens:
- bendamustine + rituximab
- fludarabine + rituximab
What is the prognosis with diffuse large B cell lymphoma?
- Aggressive - short survival (weeks to months) if therapy is not initiated
- Responsive to treatment - many will be cured
Clinical presentation of of diffuse large B cell lymphoma
- rapid and progressive lymphadopathy
- B symptoms
- extranodal involvement
Treatment of diffuse large B cell lymphoma
- RCHOP +/- radiation (early stage)
- EPOCH + rituximab