4. LEUKEMIA:
• Leukemia is a production of abnormal leukocytes either as a primary or secondary
process.
• Based on the rapidity of proliferation, they can be classified as acute or chronic,
and myeloid or lymphoid based on the originator cell.
5. ● Normal hematopoiesis involves
the tightly regulated
proliferation and maturation of
pluripotent hematopoietic stem
cells to become mature myeloid
and lymphoid peripheral blood
cells.
6.
7. ● AML comprises a group of hematological malignancies that arise from
the precursors of the myeloid, monocytoid, erythroid, and megakaryocytic
cell lineages.
● There is clonal expansion of myeloid precursor cells with a reduced capacity
to differentiate and therefore are non-functional.
● Expansion is limited to the myeloid cell line
8.
9. ● Acquired oncogenic mutations that impede differentiation, leads to the
accumulation of immature myeloid blasts in the marrow.
● The replacement of the marrow with blasts produces marrow failure and
complications related to anemia, thrombocytopenia, and neutropenia.
● AML is the most common (80 -90%) adult leukemia and accounts for 45% of
all leukemias.
● AML occurs at all ages, but the incidence rises throughout life, peaking after
60 years of age.
10. ● The diagnosis of AML is based on the presence of at least 20% myeloid blasts
in the bone marrow.
● Auer rods, distinctive needle-like azurophilic granules, are present in many
cases; they are particularly numerous in AML with the t(15;17) (acute
promyelocytic leukemia)
15. In normal hematopoiesis, myeloblast is an immature precursor of myeloid white
blood cells which will gradual mature into mature white blood cells.
In AML, a single myeloblast genetic changes which “freezes” the cell in its
immature state and prevents differentiation.
When such differentiation arrest is combined with other mutations that disrupt
genes controlling proliferation, the result is an uncontrolled growth of
immature clone cells, leading to clinical entity of AML.
19. ● The diagnosis of AML is based on the presence of at least 20% myeloid blasts
in the bone marrow.
● Myeloblasts have delicate nuclear chromatin, two to four nucleoli, and more
voluminous cytoplasm than lymphoblasts
● The cytoplasm often contains fine, peroxidase-positive azurophilic granules.
● Auer rods, distinctive needle-like azurophilic granules, are present in many
cases; they are particularly numerous in AML with the t(15;17) (acute
promyelocytic leukemia)
20. ● The number of leukemic cells in the blood is highly variable.
● Blasts may be more than 100,000/mm3, but are under 10,000/mm3 in about
50% of patients.
● Occasionally, blasts are entirely absent from the blood (aleukemic leukemia).
● For this reason, a bone marrow examination is essential to exclude acute
leukemia in pancytopenic patients.
23. ● Acute leukemias have traditionally been classified using the French-American-
British (FAB) morphologic criteria.
AML and its subtypes can most often be identified microscopically by the
presence of Auer rods,
staining for myeloperoxidase or monocyte-associated esterases, and
other cytologic features of differentiation.
24.
25. ● The FAB assignment of subtypes was replaced by the World Health
Organization (WHO) classification scheme for myeloid neoplasms.
● The WHO classification creates four key subgroups:
○ AML with recurrent genetic abnormalities (including t(8;21), inv(16),
t(15;17), t(9;11) among others),
○ AML with myelodysplasia-related changes,
○ therapy-related myeloid neoplasms, and
○ AML not otherwise specified.
26. ● The new subgroups are meant to highlight meaningful biologic and genetic
differences between disease entities with differing prognoses and clinical
behavior.
● In addition, in the WHO scheme, the number of blasts in the blood or bone
marrow required to confirm a diagnosis of AML is 20%, instead of the 30%
specified by the older FAB criteria.
● The WHO classification has been recently updated in 2016, reflecting
advances in molecular subtyping
27.
28. CYTOGENETICS
● Cytogenetic analysis has a central role in the classification of AML.
● Karyotypic aberrations are detected in 50% to 70% of cases with standard
techniques and in approximately 90% of cases using special high-resolution
banding.
● AMLs arising de novo in younger adults are commonly associated with
balanced chromosomal translocations, particularly
○ t(8;21),
○ inv(16),
○ t(15;17).
29. ○ AMLs following myelodysplastic syndromes or exposure to DNA-
damaging agents (such as chemotherapy or radiation therapy) -
○ deletions or monosomies in chromosomes 5 and 7
○ usually lack chromosomal translocations.
○ The exception to this rule is AML occurring after treatment with
topoisomerase II inhibitors, associated with translocations involving the
MLL gene on chromosome 11q23.
31. Nonspecific symptoms that begin gradually, or abruptly, are due to
● anemia,
● leukocytosis, leukopenia/leukocyte dysfunction, or
● thrombocytopenia.
Nearly half of the patients have symptoms for ≤3 months before the leukemia is
diagnosed.
32. ● Fatigue
● Anorexia
● Weight Loss
● Fever with or without an identifiable infection is the
initial symptom in ∼10% of patients.
● Opportunistic infections(eg pseudomonas) are also
common
● Bleeding, Easy Bruising, cutaneous Petechiae And
Ecchymoses
● Gum Hypertrophy
● Bone pain
● Headache
● Diaphoresis
33. ● tumors with monocytic differentiation often infiltrate the skin (leukemia cutis)
and the gingiva;
● May present as localised soft tissue masses known as myeloblastoma,
granulocytic sarcoma, or chloroma.
34. ON EXAMINATION:
● Hepatomegaly
● Splenomegaly
● Lymphadenopathy
● DIC-Associated Minor hemorrhages, gastrointestinal bleeding, intrapulmonary
hemorrhage, or intracranial hemorrhage are seen in Acute Promyelocytic
Leukemia.
● Retinal hemorrhages are detected in 15% of patients.
● Infiltration of the gingiva, skin, soft tissues, or meninges with leukemic blasts
at diagnosis is characteristic of the monocytic subtypes and those with 11q23
chromosomal abnormalities.
36. BASELINE INVESTIGATIONS:
● CBC
● Liver and Kidney function tests
● Serum LDH levels
● Clotting/Bleeding time
● PT-INR
● HLA-typing in case the patient needs to be taken for hematopoietic stem cell
transplantation
● NCCT head to rule out CNS involvement
37. PERIPHERAL BLOOD:
● Normocytic, normochromic anemia that can vary in severity.
● The reticulocyte count is normal or decreased.
● 75% of patients have platelet counts below 100,000 cells/microL, 25% will
have counts below 25,000 cells/microL. Both morphologic and functional
platelet abnormalities may be seen.
38. ● The median leukocyte count at diagnosis is 15,000 cells/microL;
○ 20 % have a count > 100,000 cells/microL and
○ 25 -40% have a count< 5000 cells/microL.
● The vast majority of patients (95 percent) will have circulating myeloblasts
that can be detected on the peripheral smear.
39. ● Myeloblasts are immature cells with large nuclei, usually with prominent
nucleoli, and a variable amount of pale blue cytoplasm (sometimes with faint
granulation) after staining with Wright Giemsa.
● The nuclear to cytoplasmic ratio and morphology vary depending upon the
maturity of the cell.
40. ● Auer rods, which are pathognomonic of myeloblasts, vary in frequency
depending upon the AML subtype.
● They can be identified as pink/red rod-like granular structures in the
cytoplasm .
● Sometimes the Auer rods are multiple, and sometimes they form a dense
clump and are referred to as "Auer bodies”
41. Bone marrow biopsy and aspirate:
● The preferred biopsy location in adults is the posterior superior iliac crest
● The sternum is another site for bone marrow aspiration
● The bone marrow is usually hypercellular due to a partial or almost total
replacement of the normal cellular components of the marrow by immature or
undifferentiated cells.
● AML can sometimes present with a hypocellular marrow.
● In patients with a dry tap (Punctio Sicca)
○ Bone marrow trephine biopsy is indicated.
42. ● The bone marrow biopsy of patients with AML is infiltrated with a
monotonous leukemic (blast) population.
● Blasts include
○ myeloblasts,
○ monoblasts,
○ promonocytes,
○ abnormal promyelocytes, and
○ megakaryoblasts.
● Pro-normoblasts are blast equivalents only in pure erythroid leukemia.
● In the current World Health Organization classification system, blast forms
must account for at least 20 percent of the total cellularity
43. ● The presence of a myeloid sarcoma is also diagnostic of AML, independent of
the blast count.
● The presence of these genetic abnormalities are considered diagnostic of
AML without regard to the blast count:
○ AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO)
○ AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
○ APL with t(15;17)(q24.1;q21.1); PML-RARA
44.
45. ● For patients with neurologic findings (eg, headache, confusion, cranial
neuropathy) and certain higher-risk features, evaluation for potential CNS
involvement.
● For patients with neurologic findings consistent with CNS bleeding,
leptomeningeal disease, and/or mass lesions, magnetic resonance imaging
(MRI) should be performed urgently.
● Lumbar puncture (LP) should be performed after correction of any
coagulopathy or severe thrombocytopenia and bleeding and mass lesions
have been excluded.
51. INDUCTION THERAPY:
● It is ideal to start therapy immediately after the patient is deemed medically
fit.
● Remission induction therapy with a seven-day continuous infusion of
cytarabine plus an anthracycline for three days -"7+3 therapy"
○ Cytarabine 100 to 200 mg/m2 daily as a continuous infusion for 7 days
○ Daunorubicin 60 to 90 mg/m2 on days 1 to 3 or Idarubicin 12 mg/m2 on
days 1 to 3
○ Treatment with 7+3 therapy generally achieves a complete remission
(CR) rate of 60 to 80 % for patients <60 to 65 years old
TI An update of current treatments for adult acute myeloid leukemia.
AU Dombret H, Gardin C
SO Blood. 2016;127(1):53. Epub 2015 Dec 10.
52. Daunorubicin versus Idarubicin
● The three-arm ALFA-9801 trial randomly assigned 468 patients 50 to 70
years old (median age 60 years) to
○ daunorubicin 80 mg/m2 once daily for three days
versus
○ idarubicin 12 mg/m2 once daily for three days
versus
○ idarubicin 12 mg/m2 once daily for four days
● rates of CR were 70 versus 83 versus 78 percent, respectively, but OS, event-
free survival (EFS), and relapse incidence did not differ between arms
● A systematic review and meta-analysis reported no difference between
daunorubicin and idarubicin with regard to overall mortality or early death
TI Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis.
AU Teuffel O, Leibundgut K, Lehrnbecher T, Alonzo TA, Beyene J, Sung L
SO Br J Haematol. 2013 Apr;161(2):192-203. Epub 2013 Feb 8.
53. ● Patients require aggressive intravenous hydration; monitoring for cardiac,
renal, and liver dysfunction; blood product support; and surveillance for
infections.
● Treatment with 7+3 therapy generally causes three to five weeks of profound
cytopenias and associated risks of life-threatening infections and bleeding.
● Other side effects include
○ nausea and vomiting,
○ mucositis/stomatitis,
○ alopecia, and
○ diarrhea.
54. ● Cytarabine may cause a flu-like syndrome (including fever and/or rash)
● Daunorubicin can be associated with infusion reactions and cardiac
arrhythmias.
55. ● Bone marrow examination should be performed 14 to 21 days after initiation
of therapy to assess the initial response to therapy and determine whether a
second induction course is needed
○ Hypoplastic – Bone marrow cellularity <5 to 20 percent and <5 percent
blasts
○ Indeterminate – Bone marrow cellularity <5 to 20 percent with ≥5
percent blasts
○ Persistent leukemia – Some clearing of leukemia or no response, but
Blast cellularity ≥20 percent
● Another examination at 4 to 5 weeks is considered for remission assessment.
56. ● Hypoplastic – Observation for two to four weeks until recovery of blood
counts. If pancytopenia persists, then repeat bone marrow biopsy.
● Indeterminate – Repeat the bone marrow examination one to two weeks later-
subsequent management guided by whether the repeat study demonstrates
hypoplasia versus persistent leukemia
● Persistent leukemia – Repeat treatment with 7+3 therapy, or treat with a more
intensive or alternate induction therapy (eg, HiDAC i.e. high dose cytarabine-
based therapy, hypomethylating agent plus venetoclax)
57. ● Those with persistent disease may receive more intensive/alternate treatment
○ high dose cytarabine [HiDAC] plus mitoxantrone;
○ mitoxantrone, etoposide, and cytarabine [MEC regimen]
TI Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.
AU Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T,
Niederwieser D, Ossenkopp +
ele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD
SO Blood. 2017;129(4):424. Epub 2016 Nov 28.
58. Adding a third agent to 7+3:
● Mutations in FLT3 due to internal transmembrane duplications (FLT3-ITD) or
changes in the activating loop of the kinase domain (FLT3-TKD) are common
in AML.
● A high mutation fraction of FLT3-ITD molecules on the surface of leukemia
cells is associated with adverse outcomes and short remissions.
● Midostaurin is added to 7+3 therapy rather than 7+3 therapy alone, based on
superior outcomes and modest incremental toxicity.
● Dose: 50 mg orally twice daily on days 8 through 21
TI Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.
AU Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB,
Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A,
Serve H, Ehninger G, Amadori S, Larson RA, Döhner H
SO N Engl J Med. 2017;377(5):454. Epub 2017 Jun 23.
59. Adding a third agent to 7+3:
● Addition of the multi-kinase inhibitor, Sorafenib, to 7+3 improved median EFS
(21 versus 9 months, respectively) and three-year EFS (40 versus 22%)
● It was associated with increased toxicity
○ fever,
○ diarrhea,
○ bleeding,
○ cardiac events,
○ hand-foot syndrome, and
○ rash
TI Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia
(SORAML): a multicentre, phase 2, randomised controlled trial.
AU Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-
Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J,
Kaiser U, Link H, Geer T, Reichle A, JunghanßC, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S,
Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G, Study Alliance Leukaemia
SOLancet Oncol. 2015 Dec;16(16):1691-9. Epub 2015 Nov 6.
60. POST REMISSION OR CONSOLIDATION THERAPY:
● HIDAC Regimen:
○ Inj Cytarabine 2g/m2 every 12 hrs x 6 days or 3g/m2 every 12 hrs x 4 days
with
○ Inj Idarubicin12mg/ m2 Or Daunorubicin 50mg/ m2 X 3 Days
○ Inj Etoposide 50mg/ m2(days1-5)
61. POST REMISSION OR CONSOLIDATION THERAPY:
● inj fludarabine 30mg/m2 ( day2-day6)
● inj cytarabine 2g/m2 over 4 hrs starting 4 hours after fludarabine(day2- day 6)
● inj idarubicin 8mg/m2 (day 4-day6)
● with G-CSF support on days 1-7.
Recommended in patients with impaired cardiac function
62. OTHER AGENTS:
● Gemtuzumab ozogamicin – GO is an immunoconjugate (anti-CD33 monoclonal
antibody linked to calicheamicin) that may improve outcomes when added to
7+3 therapy for CD33-positive AML
● Etoposide
● Cladribine
● Oblimersen (antisense BCL2 oligonucleotide)
● Topotecan
● Fludrabine
● thioguanine,
● vorinostat,
● clofarabine
● venetoclax
63.
64. ● Azacitidine 75 mg/m2 daily intravenously (IV) or subcutaneously for the first 7
days of each 28-day cycle.
or
● Decitabine 20 mg/m2 IV on days 1 to 5 of each 28-day cycle.
Plus
● Venetoclax – In cycle 1 only, Venetoclax should be administered according to
the following dose escalation schedule, to lessen the risk of TLS. Venetoclax
should be taken orally with food.
● -Cycle 1, day 1: 100 mg
● -Cycle 1, day 2: 200 mg
● -Cycle 1, days 3 to 28: 400 mg
65. ● Subsequent cycles can be started with T venetoclax 400mg from day 1.
● 28 day cycles are administered for better chances of complete response.
66. Isocitrate Dehydrogenase mutation:
●For IDH1-mutated AML, Ivosidenib monotherapy is well-tolerated and can induce
durable remissions and transfusion-independence. Ivosidenib is not available in all
medical settings.
● Ivosidenib is administered 500 mg once daily by mouth, with or without food;
high-fat meals should be avoided.
● IDH2 mutation – Enasidenib is an inhibitor of IDH2
● Enasidenib is administered 100 mg once daily by mouth for a minimum of six
months (to allow time for clinical response) and should be continued until
disease progression or unacceptable toxicity.
● The dose should be reduced for elevated bilirubin.
67. ● Low-dose cytarabine —
○ Low-dose cytarabine (LoDAC) has limited therapeutic efficacy in AML.
○ Considered acceptable for patients who are not candidates for HMA-
based treatment (eg, patients who are medically-unsuitable or
previously received HMA therapy) and do not have an actionable
mutation (eg, IDH mutation).
○ LoDAC may be ineffective for patients with higher-risk AML (ie, adverse
cytogenetic and/or molecular features).
○ Single-agent LoDAC is generally administered subcutaneously 20 mg
twice daily for 10 to 14 days every 28 days .
○ The dose may require adjustment for severe liver impairment.
68. LoDAC combination therapy:
● To lessen the risk for TLS, when venetoclax is administered with LoDAC (20
mg/m2 once daily for 10 days in 28-day cycles), the following dose-escalation
schedule should be used:
•Day 1: Venetoclax 100 mg
•Day 2: Venetoclax 200 mg
•Day 3: Venetoclax 400 mg
•Day 4 and beyond: Venetoclax 600 mg
● Compared with LoDAC monotherapy, venetoclax plus LoDAC is associated
with improved rates of remission and OS and an acceptable safety profile
69. Acute Pro-myelocytic leukemia:
● Acute promyelocytic leukemia (APL) is a biologically and clinically distinct
variant of AML.
● APL was classified as AML-M3 in the French-American-British (FAB)
classification system.
● Acute Promyelocytic Leukemia with t(15;17)(q24.1;q21.1); PML-RARA in the
World Health Organization classification system
● Without treatment, APL is the most malignant form of AML, with a median
survival of less than one month
70.
71. ● The first step in the successful treatment of a patient with acute myeloid
leukemia (AML) is the attainment of a complete remission (CR), which is
characterized by :
●Normal values for absolute neutrophil count (>1000/microL) and
platelet count (>100,000/microL), and independence from red cell
transfusion.
●A bone marrow biopsy that reveals no clusters or collections of blast
cells. Extramedullary leukemia (eg, central nervous system or soft tissue
involvement) must be absent.
●A bone marrow aspiration revealing normal maturation of all cellular
components (ie, erythroid, granulocytic, and megakaryocytic series).
72. REFRACTORY DISEASE AND RELAPSE:
● Myeloablative hematopoietic stem cell transplant is the intervention of choice
in the event of refractory disease or relapse.
● HSCT much more effective if done after attaining a CR
● However, some patients may be cured with myeloablative HCT despite
residual disease at the time of HCT.
● Autologous marrow transplantation is an option for those patients who
achieve a second CR.
73. ● A pretransplant scoring system has been devised to predict the survival of
patients not in CR who undergo myeloablative HCT based on the assessment
of five criteria (maximum score 6 points)
●Duration of CR: First CR ≤6 months = 1 point
●Cytogenetics prior to HCT: Poor risk = 1 point
●Donor: Mismatched unrelated donor = 1 point; related donor other
than HLA identical sibling = 2 points
●Circulating blasts: Present = 1 point
●Karnofsky performance status: <90 = 1 point
TI Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure.
AU Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, Kamble R, Copelan E, de Lima M, Gupta V,
Keating A, Lazarus HM, Litzow MR, Marks DI, Maziarz RT, Rizzieri DA, Schiller G, Schultz KR, Tallman MS,
Weisdorf D J Clin Oncol. 2010;28(23):3730. Epub 2010 Jul 12.
74. ● Total score predicts long-term survival with relapsed or refractory AML not in
CR at the time of myeloablative HCT.
● For patients with a score of ≥3, myeloablative HCT is unlikely to be of benefit;
further induction chemotherapy may be administered to these patients in an
attempt to decrease the tumor burden and improve the performance status
prior to reconsideration of HCT.
● Myeloablative HCT without further induction chemotherapy is given if the
patient has a score ≤2 .
TI Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure.
AU Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, Kamble R, Copelan E, de Lima M, Gupta V,
Keating A, Lazarus HM, Litzow MR, Marks DI, Maziarz RT, Rizzieri DA, Schiller G, Schultz KR, Tallman MS,
Weisdorf D J Clin Oncol. 2010;28(23):3730. Epub 2010 Jul 12.
75. Conditioning Regimens:
● Myeloablative regimens – A myeloablative conditioning regimen consists of a
single agent or combination of agents expected to destroy the hematopoietic
cells in the bone marrow and produce profound pancytopenia within one to
three weeks from the time of administration.
● The resulting pancytopenia is long-lasting, usually irreversible, and in most
instances fatal, unless hematopoiesis is restored by infusion of hematopoietic
stem cells. Examples include:
● •Busulfan and cyclophosphamide
● •Melphalan, busulfan, and total body irradiation (TBI)
● •Cyclophosphamide plus TBI
76. ● Nonmyeloablative (reduced intensity) regimens –
○ A nonmyeloablative regimen is one that combines the anti-leukemia
effect of more modest doses of chemotherapy with the objective of
achieving significant immunosuppression (to allow engraftment), and
thereby causing minimal organ and mucosal damage.
Following transplant, the patient is constantly monitored for post-transplant
graft rejection as well as GVHD.
77. Relapse after HCT:
● All patients who might be candidates for a second HCT should receive
reinduction chemotherapy first. This establishes that they still have
chemotherapy-sensitive disease. Only those responding to treatment (usually
no more than 50 percent) should proceed to a second transplant
TI The role of repeat transplantation of haemopoietic stem cells and adoptive immunotherapy in treatment
of leukaemia relapsing following allogeneic transplantation.
AU Locatelli F
SO Br J Haematol. 1998;102(3):633.
78. ● Relapsing patients may receive a second transplant following reduced
intensity conditioning .
● In one series, seven patients with AML relapsing after an allograft were
treated with the FLAG regimen (fludarabine, high dose Ara-C, G-CSF) with or
without an anthracycline, followed by a second allogeneic HCT from the
original donor .
● CR was attained in six with no treatment-related mortality. Median duration
of the second CR was 14 months, which was slightly longer than the first CR of
11 months. Chronic GVHD was extensive in four of the seven.
TI Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG +/- Ida) and
second allogeneic stem cell transplant.
AU Pawson R, Potter MN, Theocharous P, Lawler M, Garg M, Yin JA, Rezvani K, Craddock C, Rassam S, Prentice HG
SO Br J Haematol. 2001;115(3):622.
79. CNS INVOLVMENT IN AML:
● Risk factors — CNS involvement is more common in patients with AML with
the following features:
●Clinical features:
•Hyperleukocytosis (>100,000/microL)
•Age <2 years
•Elevated lactate dehydrogenase (LDH)
●Leukemic factors:
•Prominent monocytic component (eg, acute monoblastic/monocytic
leukemia or acute myelomonocytic leukemia)
•Acute promyelocytic leukemia (APL) with PML:RARA in relapse
•Molecular/cytogenetic findings, such as FLT3-internal tandem
duplication, AML with inv(16) or chromosome 11 abnormalities, complex
karyotype
•Expression of CD56 (adhesion molecule) on leukemia blast cells
80. PATHOGENESIS:
● Extension from the bone marrow of the skull through bridging veins into the
subarachnoid space
● Contamination of the cerebrospinal fluid (CSF) via the choroid plexus
● Invasion of the brain parenchyma via brain capillaries
● Direct infiltration of the leptomeninges through bony lesions of the skull
● Iatrogenic introduction of blasts into the CSF at the time of lumbar puncture
81. MANAEMENT:
● Asymptomatic leptomeningeal involvement — For patients with
leptomeningeal involvement, but no signs of neurologic deficit (eg, no cranial
nerve impairment or other neurologic findings),
INTRATHECAL chemotherapy alone, rather than systemic chemotherapy or
cranial RT.
82. ● Leptomeningeal involvement with neurologic findings — For patients with
cranial nerve abnormalities or other neurologic impairment associated with
leptomeningeal involvement,
○ treatment with IT chemotherapy plus RT and/or systemic chemotherapy
that penetrates the CNS.
● RT is quickest and most reliable way to salvage a cranial nerve, which is
typically compressed in the neural foramen.
83. ● Mass lesion — A mass lesion of the brain, spine, or a paraspinous mass that
threatens the spinal cord generally requires RT and/or surgical debulking to
reduce or prevent neurologic symptoms.
● The choice of approach by the location and size of the mass, nature of
neurologic symptoms.
● Treatment with a glucocorticoid (eg, dexamethasone, prednisone) should be
considered for all patients who have vasogenic edema or symptoms related to
peritumoral edema
84. INTRATHECAL CHEMOTHERAPY:
● Intrathecal (IT) therapy involves injection of chemotherapy into the
cerebrospinal fluid (CSF).
● IT therapy can be injected into the lumbar thecal sac by lumbar puncture (LP)
or directly into the lateral ventricle through a subcutaneous reservoir and
ventricular catheter (eg, Ommaya reservoir)
Working: To insert an Ommaya reservoir, the physician drills a burr hole and
inserts the device's catheter through the patient's nondominant frontal lobe into
the lateral ventricle. The reservoir, which has a self-sealing silicone injection
dome, rests over the burr hole under a scalp flap. This creates a slight, soft bulge
on the scalp about the size of a quarter. Usually, drugs are injected into the dome
with a syringe.
85. ● An equivalent volume of CSF (eg, 7 to 10 mL) should be removed prior to
instilling IT chemotherapy; many patients have rapid relief of symptoms
related to increased intracranial pressure as fluid is removed.
● Treatment should be administered slowly (over several minutes) to reduce the
risk of vomiting.
86. ● Methotrexate – Treat with 15 mg/dose when administered via an LP, or 12 mg
when administered via an Ommaya reservoir.
● To reduce the local chemical arachnoiditis, add 50 mg of hydrocortisone to
preservative-free methotrexate and administer treatment slowly.
● Injecting into an Ommaya often results in projectile vomiting (perhaps due a
pressure effect on the chemoreceptor area on the medial wall of the lateral
ventricle).
● Adverse effects of IT methotrexate include chemical (aseptic) meningitis,
delayed leukoencephalopathy, acute encephalopathy, and transverse
myelopathy
87. ● Cytarabine – 50 mg/dose via LP or 40 mg via Ommaya.
● IT cytarabine may be associated with chemical (aseptic) meningitis and, less
often, with encephalopathy,
88. ● Initial treatments – IT treatment is given two to three times per week until the
CSF has been cleared of the leukemic cells, which generally occurs after a few
treatments.
● After clearing blasts from CSF – Subsequent treatment is given at weekly
intervals for two more doses, followed by monthly administration, for a total
of one year.
89. RADIOTHERAPY:
● Treatment field – To avoid excess myelosuppression, cranial RT is preferred
rather than craniospinal RT.
● The treatment field should include the base of the brain (typically down to C2)
to adequately cover the foramina for the cranial nerves.
● And posterior one third of globe of the eyes are also included in the field
because subarachnoid space extends as a sheath along the optic nerve.
● Lower extremity weakness- lumbosacral spine RT in addition to cranial RT,
particularly if there is nerve involvement at this level.
● Dose and timing –
18 to 25 Gy for the brain as soon as CNS involvement is suspected.
90. Chloroma
● Solid masses of leukemic infiltrates are responsive to modest doses of RT.
● The name chloroma derives from the fact that myeloid cells contain
myeloperoxidase, which manifests a greenish color on gross inspection.
● These may occur in all varieties of extramedullary sites including periosteum,
skin, soft tissues, gastrointestinal tract, the spine, and in epidural spaces or
meninges
● symptomatic problems from chloromas may be readily relieved with doses of
10 to 24 Gy
91. CONCURRENT THERAPY:
● IT therapy – two or three times per week while the patient is receiving cranial
RT for a cranial neuropathy.
● Systemic therapy –concurrent high-dose systemic chemotherapy (ie, with
methotrexate or cytarabine) for two weeks before or after cranial RT is
avoided.
● Concurrent therapy may be acceptable for RT at other sites (eg, a lumbar or
sacral mass).
● Concurrent administration of an anthracycline with RT usually results in
increased skin toxicity.
92. Systemic chemotherapy:
● Systemic chemotherapy that penetrates the CNS can serve as an adjunct to IT
treatment.
● High-dose methotrexate or cytarabine can reduce the CNS tumor load .
● The relapse rate, even after initially rapidly successful therapy, is high, either
in association with bone marrow relapse or independently.
94. DIFFERENTIATION SYNDROME:
● Differentiation syndrome (DS) is a treatment complication of ATRA that
requires urgent management with systemic glucocorticoids to prevent
progressive respiratory or renal insufficiency, heart failure, and other life-
threatening complications.
● It is caused by a large, rapid release of cytokines (immune substances) from
Leukemia cells that are affected by the anticancer drug
● DS is most often caused by treatment of AML with inhibitors of
○ treatment of acute promyelocytic leukemia with all-trans retinoic acid
(ATRA) and/or
○ arsenic trioxide (ATO).
○ isocitrate dehydrogenase (IDH; eg, ivosidenib, enasidenib)
95. It generally presents several days to 1-2 weeks after treatment initiation with
■ fever,
■ peripheral edema,
■ hypotension,
■ weight gain, and/or
■ Pleural/pericardial effusions.
■ Laboratory studies usually reveal leukocytosis (which may include a rapid
increase in blast count), acute renal failure, radiographic opacities, and/or
pleuro-pericardial effusion.
96. ● Primary treatment: Systemic Glucocorticoids.
Treatment may also include hydroxyurea to control leukocytosis and/or temporary
discontinuation of the antileukemic therapy
● Supportive care generally includes
○ empiric antibiotics,
○ fluid management, and
○ supplemental oxygenation;
○ severe cases may require renal replacement therapy or mechanical
ventilation.
97. HYPERLEUKOCYTOSIS AND LEUKOSTASIS
● Hyperleukocytosis has been defined in the setting of AML as a total white
blood cell count greater than 50,000/microL .
● It is present in 10 to 20 percent of patients with newly diagnosed AML.
● Symptomatic hyperleukocytosis (ie, leukostasis), typically presenting with
respiratory or neurological distress, constitutes a medical emergency.
● An absolute myeloblast count approaching 100,000/microL is a medical
emergency even in the asymptomatic patient.
98. METABOLIC ABNORMALITIES:
● Tumor lysis syndrome — Tumor lysis syndrome, caused by rapid leukemic cell
death following the onset of chemotherapy, can be seen in patients with AML,
especially those with hyperleukocytosis, impaired baseline renal function, and
hyperuricemia at the time of diagnosis
99. ● Tumor lysis syndrome is characterized by
○ hypocalcemia,
○ hyperphosphatemia,
○ hyperuricemia,
○ hyperkalemia, and
○ renal insufficiency.
Release of large amounts of phosphate from lysed blasts, which
coprecipitates with calcium in the kidneys, leads to hypocalcemia and
sometimes to oliguric renal failure.
100. ● LACTIC ACIDOSIS:
Rare both at the time of presentation and relapse
anaerobic metabolism by the leukemic cells at sites of leukostasis
The prognosis of this complication is grave;
chemotherapy, if effective, corrects the acute acidosis.
Azacitidine: chemical analog of cytidine, a nucleoside in DNA and RNA
Decitabine: nucleic acid synthesis inhibitor. And analog of cytidine
Venetoclax : B-cell lymphoma-2 (BCL-2) inhibitors
