Hematological Malignancies

erythrocytes, platelets, monocytes, basophils, neutrophils, eosinophils

T- lymphocytes and B-lymphocytes

• Intermediate cell types that develop from stem cells but have not fully matured yet into erythrocytes, lymphocytes, etc.
• Normal is less than 5% blasts

presence of at least 20% leukemic blasts in the bone marrow or blood

By disease acuity and cell of origin

• Oncogene activation leading to increased proliferation
• Loss of signals for differentiation
• Loss of tumor suppressor genes
• Loss of apoptosis signals

they're rapidly progressive and can lead to death within weeks to months without treatment

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)

• ALL
• (CNS involvement also possible with AML - M4 and M5 subtypes)

older adults

• anemia
• thrombocytopenia
• leukopenia/leukocytosis - fever, infections
• hyperuricemia
• incr K and PO4
• bone pain
• seizures
• diplopia
• Auer rods
• gum hypertrophy (M4, M5)
• infiltration of gingivae, skin, soft tissues, or meninges (M4, M5)
• organomegaly
• lymphadopathy

lymphoma - very limited use in leukemia

promptly after diagnosis - within 72 hours

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

• 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

• myelosuppression
• n/v
• mucositis
• High dose: cerebellar tox (slurred speech, mystagmus, dysmetria); conjunctivitis/keratitis

• myelosuppression
• n/v
• mucositis
• cardiac toxicity
• urine discoloration

• 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

• 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.

M3

M3 - APL

• younger patients (diagnosis typically betw 15 -60 yo)
• risk factors - younger age, hispanic origin, obesity

PML-RAR fusion protein

• severe coagulopathy characterized by DIC
• however, pt is at risk of bleeding b/c all clotting factors are used up

• ATRA + anthracycline (dauno or ida) +/- cytarabine
• ATRA + As2O3

• 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)

nilotinib

• QT prolongation
• APL differentiation syndrome
• peripheral neuropathy
• fatigue
• weight gain

• 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

myeloid growth factors

bimodal distribution - kids under 10 and adults over 50

• 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

• Anemia
• Thrombocytopenia
• Leukopenia or leukocytosis
• Hyperuricemia
• Incr K and PO4
• Decr Ca++
• splenomegaly
• hepatomegaly
• lymphadopathy
• testicular enlargement
• chloromas (small, blue-green collections of leukemia cells under the skin)

• Any combo of:
• Asparaginase
• Anthracycline
• Cyclophosphamide
• Corticosteroid
• Cytarabine
• Vincristine

• 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

vincristine

• bleding or thrombosis
• acute anaphylaxis
• severe pancreatitis

• Myelosuppression, n/v, secondary leukemias, sterility, infertility
• Hemorrhagic cystitis - use MESNA

• 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.

older adults

• the Philadelphia chromosome (Ph)
• BCR-ABL - abnormal fusion protein
• (can also be seen in adults with ALL and rarely in AML)

encodes for mutant tyrosine kinase which leads to uncontrolled cell proliferation, inhib of apoptosis, accumulation of malignant cells

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

• leukocytosis
• thrombocytosis (incr platelets)
• basophilia
• hyperuricemia
• incr LDH and B12
• fever
• night sweats
• LUQ/abdominal pain
• splenomegaly
• hepatomegaly
• 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

• Primary resistance (lack of efficacy) - switch to nilotinib or dasatinib
• Secondary resistance (loss of efficacy over time) - increase imatinib dose to overcome the resistance

• 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

• 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)

• lymphoma
• lymphocytic leukemia

solid

• Hodgkin's lymphoma
• Non-Hodgkin's lymphoma

B symptoms: fever (T. 100.4), drenching night sweats, and weight loss (> 10% of body weight)

bimodal distribution - 15-30 and >55

• 1. Classical HL (95%) - presence of Reed-Sternberg cells
• 2. Lymphocyte-Predominant HL (5%) - lack of Reed-Sternberg cells

• lymphadenopathy (usually painless - rubbery mass)
• Systemic B symptoms
• chronic pruritis
• extranodal involvement (spleen, lungs, liver, bone marrow)

• 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

any age, but primarily seen in elderly

• Burkitt's lymphoma
• follicular B cell lymphoma
• mantle cell lymphoma

older adults

• CLL
• (if the involvement is nodal instead of marrow/blood, it is SLL)

• often asymptomatic in early disease
• anemia
• thrombocytopenia
• lymphocytosis
• fatigue
• B symptoms (fever, weight loss, night sweats)
• splenomegaly
• hepatomegaly
• lymphadenopathy
• frequent infx
• autoimmune disease
• secondary malignancy
• Richter transformation (goes from indolent to aggressive form)

• 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

• 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

Non-Hodgkin's

• it is indolent and relatively benign, so relatively long survival
• responsive to tx, but pts are rarely cured

• waxing/waning
• painless lymphadenopathy
• splenomegaly
• bone marrow involvement
• usually no B symptoms

• Observation
• Radiation
• Chemo +/- Radiation

• rituximab-based regimens:
• bendamustine + rituximab
• RCHOP
• RCVP
• fludarabine + rituximab
• RFND

• radioimmunotherapy:
• zevalan
• bexxar

• Aggressive - short survival (weeks to months) if therapy is not initiated
• Responsive to treatment - many will be cured

• rapid and progressive lymphadopathy
• B symptoms
• extranodal involvement

• RCHOP +/- radiation (early stage)
• EPOCH + rituximab