adult acute lymphocytic leukemia adult acute lymphocytic leukemia jaya v.juturi md 5/5/2004

Adult acute lymphocytic Adult acute lymphocytic leukemialeukemia

Jaya V.Juturi MDJaya V.Juturi MD

5/5/20045/5/2004

JMJM

35 year old Hispanic male patient 35 year old Hispanic male patient

2 week history of generalized malaise and pallor 2 week history of generalized malaise and pallor

One week history of easy bruisabilityOne week history of easy bruisability

No relevant medical or surgical historyNo relevant medical or surgical history

No high risk behavior, non-smoker, has 8 siblingsNo high risk behavior, non-smoker, has 8 siblings

..

JMJM

No fevers, gum bleeding, chills, No fevers, gum bleeding, chills,

Five pound weight loss over a week to 10 daysFive pound weight loss over a week to 10 days

Ecchymoses and oral thrush Ecchymoses and oral thrush

Otherwise exam normal, no lymphadenopathy, Otherwise exam normal, no lymphadenopathy, hepatosplenomegalyhepatosplenomegaly

WBC 6.1, Hgb 3.2, Plts 4000WBC 6.1, Hgb 3.2, Plts 4000

Acute Lymphocytic LeukemiaAcute Lymphocytic Leukemia

Incidence is about 3000-4000 cases a yearIncidence is about 3000-4000 cases a year

2/3 of these occur in children2/3 of these occur in children

80% of children are cured80% of children are cured

35-40% adults with ALL survive 2 years35-40% adults with ALL survive 2 years

Acute Lymphocytic LeukemiaAcute Lymphocytic Leukemia

Only 30% adults curedOnly 30% adults cured

Biology of the disease appears to be differentBiology of the disease appears to be different

Intensive chemotherapy and CNS prophylaxis contribute Intensive chemotherapy and CNS prophylaxis contribute to most cures!to most cures!

Accurate diagnosis is crucial and an experienced Accurate diagnosis is crucial and an experienced hematopathologist should always be involvedhematopathologist should always be involved

Pui, C.-H. et al. N Engl J Med 1998;339:605-615

Kaplan-Meier Analyses of Event-free Survival (Top Panel) and Overall Survival (Bottom Panel) in 2255 Children with ALL in 13 Consecutive Studies Conducted at St

Morphology VS ImmunophenotypeMorphology VS Immunophenotype

ALL can develop from any lymphoid cell blocked from maturationALL can develop from any lymphoid cell blocked from maturation

Most sensitive B-cell marker is CD 19, CD 7 for T-cell lineage, CD-Most sensitive B-cell marker is CD 19, CD 7 for T-cell lineage, CD-13 or CD 33 for myeloid cells13 or CD 33 for myeloid cells

Cytoplasmic CD 79a for B-cells, CD3 for T-cells and myelo Cytoplasmic CD 79a for B-cells, CD3 for T-cells and myelo peroxidase fro myeloid cellsperoxidase fro myeloid cells

TdT elevated in most ALLTdT elevated in most ALL

Accurate diagnosis in 99% cases with the above described methodsAccurate diagnosis in 99% cases with the above described methods

Morphology VS ImmunophenotypeMorphology VS Immunophenotype

Aberrant myeloid antigen expression can be seen in about a third of Aberrant myeloid antigen expression can be seen in about a third of the adults with ALLthe adults with ALL

20% AML cases may have an elevated TdT20% AML cases may have an elevated TdT

ALL ALL B-cell lineage 80%B-cell lineage 80%

T-cell lineage 10-15%T-cell lineage 10-15%

FAB classificationFAB classification

Cellular classification (FAB)Cellular classification (FAB)

L-1 mature appearing lymphoblastsL-1 mature appearing lymphoblasts

L-2 pleomorphic lymphoblastsL-2 pleomorphic lymphoblasts

L-3 is most B-cell ALLL-3 is most B-cell ALL

95% of all acute lymphocytic leukemias except B-cell 95% of all acute lymphocytic leukemias except B-cell type have and elevated TdT expression (terminal type have and elevated TdT expression (terminal deoxynucleotidyl transferase expression)deoxynucleotidyl transferase expression)


Transformation of Hematopoietic Cells in the Pathogenesis of ALL

Risk assessmentRisk assessment

Adults Adults

Hyperleukocytosis at presentationHyperleukocytosis at presentation

Adverse cytogenetic profileAdverse cytogenetic profile

CNS or Testicular involvement at presentationCNS or Testicular involvement at presentation

Pre-T cell leukemia and resistance to chemotherapyPre-T cell leukemia and resistance to chemotherapy

Delayed early response to chemotherapyDelayed early response to chemotherapy


Estimated Frequencies of Specific Genotypes among Children and Adults with ALL


Kaplan-Meier Analysis of Event-free Survival According to the Subtype of Leukemia in 467 Children with ALL Who Were Enrolled in Three Consecutive Treatment Protocols at St


Proposed Risk-Classification System for ALL According to Immunophenotype and Genotype, Age, Leukocyte Count, Early Response to Treatment, and Presence or Absence of

Extramedullary Disease (in B-Cell-Precursor Disease)

Supportive/clinical careSupportive/clinical care

At least 50% patients with Acute lymphocytic leukemia At least 50% patients with Acute lymphocytic leukemia present with fever.present with fever.

Often secondary to cytokines TNF, IL-1 and IL-6 Often secondary to cytokines TNF, IL-1 and IL-6

But in about a third this fever is secondary to an infectionBut in about a third this fever is secondary to an infection

Monitor for hyperuricemia, hyperkalemia and Monitor for hyperuricemia, hyperkalemia and hyperphosphatemia in all patients----Tumor lysis hyperphosphatemia in all patients----Tumor lysis syndromesyndrome

Supportive/clinical careSupportive/clinical care

Intravenous hydration.Intravenous hydration.

Allopurinol, cytoreductionAllopurinol, cytoreduction

?Leukapheresis, hyperviscosity?Leukapheresis, hyperviscosity

Psychosocial supportPsychosocial support

Indwelling cathetersIndwelling catheters

Transfusion support Transfusion support

TreatmentTreatment

Well designed clinical trials and multi-drug regimens Well designed clinical trials and multi-drug regimens have contributed to the cure rate have contributed to the cure rate

Fractionated high dose cytoxan, high dose methotrexate Fractionated high dose cytoxan, high dose methotrexate and cytarabine form the core of most regimens given in and cytarabine form the core of most regimens given in an intense two to eight month fashionan intense two to eight month fashion

Most regimens also routinely include dexamethasone, Most regimens also routinely include dexamethasone, vincristine, as well as asparaginase in children and vincristine, as well as asparaginase in children and anthracycline in an adultanthracycline in an adult

TreatmentTreatment

Induction of complete remission occurs in 97-99% of Induction of complete remission occurs in 97-99% of children and 75-80% of the adultschildren and 75-80% of the adults

Cranial prophylaxis or treatment is a must for all patientsCranial prophylaxis or treatment is a must for all patients

Most induction treatments are followed by maintainance Most induction treatments are followed by maintainance therapy long termtherapy long term

The role of consolidation in adults is not clearThe role of consolidation in adults is not clear

TreatmentTreatment

Granulocyte colony stimulating factors hasten Granulocyte colony stimulating factors hasten neutropenic recovery and thereby reduce complications neutropenic recovery and thereby reduce complications of chemotherapyof chemotherapy

They do not appear to improve or affect response to They do not appear to improve or affect response to chemotherapychemotherapy

Maintainance often lasts 2-3 years Maintainance often lasts 2-3 years

6-mercaptopurine and methotrexate are the most 6-mercaptopurine and methotrexate are the most commonly used drugscommonly used drugs

CNS prophylaxisCNS prophylaxis

CNS can be a potential sanctuary for leukemic cellsCNS can be a potential sanctuary for leukemic cells

Presymptomatic therapy directed towards the CNS usually with Presymptomatic therapy directed towards the CNS usually with intrathecal chemotherapy and systemic chemotherapy…intrathecal chemotherapy and systemic chemotherapy…

CNS relapse less than 2% with such therapyCNS relapse less than 2% with such therapy

Role of cranial irradiation not clear anymore…risk of neurotoxicity Role of cranial irradiation not clear anymore…risk of neurotoxicity and can occasionally cause brain tumors ? and can occasionally cause brain tumors ?

Role in high risk patients…T-cell ALL or presentation with Role in high risk patients…T-cell ALL or presentation with hyperleukocytosishyperleukocytosis


Treatment Strategies Associated with Improved Outcomes in Clinical Studies of ALL

Allogeneic stem cell transplantAllogeneic stem cell transplant

Indicated for patients who do not have a response to initial induction Indicated for patients who do not have a response to initial induction treatment and for those who relapse and go into a second remissiontreatment and for those who relapse and go into a second remission

Transplantation during the first remission remains controversialTransplantation during the first remission remains controversial

MLL gene abnormalities and BCR-ABL translocations given their MLL gene abnormalities and BCR-ABL translocations given their unfavorable prognosis are often treated with an allogeneic transplantunfavorable prognosis are often treated with an allogeneic transplant

HLA matched sibling transplant is ideal, but for those who lack HLA matched sibling transplant is ideal, but for those who lack suitable family donors a matched unrelated transplant is reasonablesuitable family donors a matched unrelated transplant is reasonable

Umbilical cord blood transplants are feasible in children and may not Umbilical cord blood transplants are feasible in children and may not require the same degree of histocompatibilityrequire the same degree of histocompatibility

JMJM

Treated with Hyper CVAD/MTX-Ara-c regimen and CNS Treated with Hyper CVAD/MTX-Ara-c regimen and CNS prophylaxisprophylaxis

Residual leukemia at the end of the first two cycles…Residual leukemia at the end of the first two cycles…

Primary refractory disease is being allo-transplanted in Primary refractory disease is being allo-transplanted in the near futurethe near future

8 siblings being typed and HLA matching in process8 siblings being typed and HLA matching in process

Results of Treatment With Hyper-CVAD, a Dose-Intensive Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia …Regimen, in Adult Acute Lymphocytic Leukemia …Journal of Journal of Clinical OncologyClinical Oncology, Vol 18, Issue 3, 2000: 547, Vol 18, Issue 3, 2000: 547

204 adult ALL patients204 adult ALL patients

Median age 40 yrsMedian age 40 yrs

T-cell disease in 17%.T-cell disease in 17%.

Leukocytosis in 26%,Leukocytosis in 26%,

Philadelphia chromosome–positive disease in 16% Philadelphia chromosome–positive disease in 16%

A mediastinal mass in 7%. A mediastinal mass in 7%.


Treatment consisted of four cycles of Hyper-CVAD Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor prophylaxis and granulocyte colony-stimulating factor therapy. therapy.

Maintenance in patients with nonmature B-cell ALL Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). vincristine, and prednisone (POMP).


91%achieved complete remission (CR) and 6% died 91%achieved complete remission (CR) and 6% died during induction therapy. during induction therapy.

Estimated 5-year survival and 5-year CR rates were 39% Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. and 38%, respectively.

The incidence of CNS relapse was low (4%). The incidence of CNS relapse was low (4%).

Survival based on Ph + statusSurvival based on Ph + status

adult acute lymphocytic leukemia adult acute lymphocytic leukemia jaya v.juturi md 5/5/2004

Documents

chemotherapy slide

st slide

fab classification slide

precursor disease slide

bcell lineage

tcell lineage

bcell type

lymphoid cell