Adult Acute Lymphoblastic Leukemia (ALL)

ALL (also called acute lymphocytic leukemia) is an aggressive type of leukemia characterized by the presence of too many lymphoblasts or lymphocytes in the bone marrow and peripheral blood. It can spread to the lymph nodes, spleen, liver, central nervous system (CNS), and other organs. Without treatment, ALL usually progresses quickly.

ALL occurs in both children and adults. It is the most common type of cancer in children, and treatment results in a good chance for a cure. For adults, the prognosis is not as optimistic. This summary discusses ALL in adults. (Refer to the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for more information about ALL in children.)

Clinical Evaluation   Staging   Treatment  

Incidence and Mortality

Estimated new cases and deaths from ALL in the United States in 2018:
• New cases: 5,960. • Deaths: 1,470.

Anatomy

ALL presumably arises from malignant transformation of B- or T-cell progenitor cells.
It is more commonly seen in children, but can occur at any age.
The disease is characterized by the accumulation of lymphoblasts in the marrow or in various extramedullary sites, frequently accompanied by suppression of normal hematopoiesis.
B- and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective lineage developments.
Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear terminal deoxynucleotide transferase (TdT).
Precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.


Molecular Genetics

Some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1). The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL. In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).

Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The bcr-abl fusion gene may be detectable only by fluorescence in situ hybridization (FISH) or reverse-transcriptase polymerase chain reaction (RT-PCR) because many patients have a different fusion protein from the one found in CML (p190 vs. p210). These tests should be performed, whenever possible, in patients with ALL, especially in those with B-cell lineage disease.

L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).

Incidence and Mortality

Estimated new cases and deaths from ALL in the United States in 2018:
• New cases: 5,960. • Deaths: 1,470.

Anatomy

ALL presumably arises from malignant transformation of B- or T-cell progenitor cells.
It is more commonly seen in children, but can occur at any age.
The disease is characterized by the accumulation of lymphoblasts in the marrow or in various extramedullary sites, frequently accompanied by suppression of normal hematopoiesis.
B- and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective lineage developments.
Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear terminal deoxynucleotide transferase (TdT).
Precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.


Molecular Genetics

Some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1). The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL. In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).

Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The bcr-abl fusion gene may be detectable only by fluorescence in situ hybridization (FISH) or reverse-transcriptase polymerase chain reaction (RT-PCR) because many patients have a different fusion protein from the one found in CML (p190 vs. p210). These tests should be performed, whenever possible, in patients with ALL, especially in those with B-cell lineage disease.

L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).

 

ALL

ALL presumably arises from malignant transformation of B- or T-cell progenitor cells.
B- and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective lineage developments.
Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear terminal deoxynucleotide transferase (TdT).
Precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.

Additional categorizations of ALL include:

Acute B lymphoblastic leukemia
Early precursor B ALL (also known as early pre-B ALL or pro-B ALL)
Pre-B ALL
Common ALL
Mature B cell ALL (also known as Burkitt leukemia)
Philadelphia-positive ALL (Ph+ ALL)

Acute T-lymphoblastic leukemia

Natural killer cell leukemia



The earliest normal B-lineage precursors expresses CD34 in combination with CD38, CD19, high levels of CD10(bright), and low levels of CD22 and lacking CD20.
Next stage of B cell down-regulates CD34 completely and CD10 partially, prior to the progressive up-regulation of CD20. CD22 levels are also increased slightly as CD20 is up-regulated.
Finally, CD10 is down-regulated completely, CD38 partially, and CD22 upgraded to high intensity.
The last stage, in which CD10 is completely down-regulated, is considered a mature stage of B-cell ; cells with this immunophenotype were not included in calculating the percent hematogones.
In addition, TdT expression parallels CD34 in the B-cell maturation sequence. Asynchronous expression of the earliest and latest antigens, eg, concurrent CD34 and CD20,and aberrant over- or under-expression of antigens was not observed in hematogone populations.



T cell -- CD3, CD4, CD8
B cell -- CD19, CD20
NK cell -- CD56
Monocyte/Macrophage -- CD14, CD33
Macrophage -- CD11b, CD68, CD163
Dendritic cell -- CD11c, HLA-Dr
Leukocyte -- CD45
Granulocyte -- CD66b
Neutrophil -- CD11b, CD16, CD18, CD32, CD44, CD55
Eosinophil -- CD45, CD125, CD193, F4/80, Siglec-8
Basophil -- CD19, CD22, CD45Low, CD123
Mast cell CD32, CD33, CD117, CD203cFCERl
Platelet -- CD41, CD61, CD62 -- CD42a, CD42b
Megakaryocyte -- CD41b, CD42a, CD42b, CD61
Erythrocyte CD 235a

Stem cell -- CD34
Endothelial cell -- CD146
Epithelial cell -- CD 326


The earliest recognizable B-lineage precursors expressed the progenitor cell marker CD34 in combination with CD38, CD19, high levels (bright) of CD10, and low levels of CD22 and lacking CD20. These progressed to the next stages by down-regulating CD34 completely and CD10 partially, prior to progressive up-regulation of CD20. CD22 levels also increased slightly as CD20 was up-regulated. Finally, CD10 was down-regulated completely, CD38 partially, and CD22 upgraded to high intensity. The last stage, in which CD10 is completely down-regulated, is considered a mature stage of B-cell development; cells with this immunophenotype were not included in calculating the percent hematogones. Although not specifically assessed in this study, TdT expression parallels CD34 in the B-cell maturation sequence. The stage of appearance of surface immunoglobulin (sIg) was not assessed; however, in our experience sIg is variable among individual cells in each case, occurring from shortly before to shortly after acquisition of a high level of CD20 expression. Asynchronous expression of the earliest and latest antigens, eg, concurrent CD34 and CD20, and aberrant over- or under-expression of antigens was not observed in hematogone populations.




CD15: Reed-Sternberg cells, neutrophils
CD30 and CD15: Reed-Sternberg cells
CD30 positive and CD15 negative: Anaplastic large cell lymphoma cells

Multiple Soures

Cell Markers

Diagnosis and Subclassification of Acute Lymphoblastic Leukemia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235437/
Current standards for acute lymphoblastic leukemia (ALL) diagnosis integrate the study of cell morphology, immunophenotype and genetics/cytogenetics as detailed in the 2008 WHO classification of lymphoid neoplasms.1 The classification originally suggested by the FAB group is no longer followed.2,3 The FAB classification was clinically useful since it permitted recognition of probable Burkitt lymphoma in leukemic phase, but it has now been replaced by the WHO classification. Lymphoid neoplasms are assigned, in the most recent WHO classification, to two principal categories: neoplasms derived from B- and T-lineage lymphoid precursors and those derived from mature B, T or NK cells. ALL belongs to the first of these major groups, designated B- or T-lymphoblastic leukemia/lymphoma4 and including three principal categories: B-lymphoblastic leukemia/lymphoma not otherwise specified, B-lymphoblastic leukemia/lymphoma with recurrent cytogenetic alterations and T-lymphoblastic leukemia/lymphoma. The designation of leukemia/lymphoma reflects the principle that these neoplasms should be classified on the basis of their biological and molecular characteristics, regardless of the sites of involvement. The leukemic variant shows diffuse involvement of the peripheral blood and the bone marrow, while lymphoma is confined to nodal or extranodal sites, with no or minimal involvement of the bone marrow. In the leukemic form, by definition, the bone marrow must contain at least 20% blast cells. A purely leukemic presentation is most typical of B-lineage ALL (85%), while cases of T-lineage disease often present with an associated lymphomatous mass in the mediastinum or other sites.

Immunophenotype of B-lineage ALL
European Group of Immunological Classification of Leukemias (EGIL)
In B-lineage ALL the most important markers for diagnosis, differential diagnosis and subclassification are CD19, CD20, CD22, CD24, and CD79a.
The earliest B-lineage markers are CD19, CD22 (membrane and cytoplasm) and CD79a. A positive reaction for any two of these three markers, without further differentiation markers, identifies pro-B ALL (EGIL B-I subtype).
The presence of CD10 antigen (CALLA) defines the “common” ALL subgroup (EGIL B-II subtype).
Cases with additional identification of cytoplasmic heavy mu chain constitute the pre-B group (EGIL B-III subtype)
, The presence of surface immunoglobulin light chains defines mature B-ALL (EGIL B-IV subtype).

Examples of ALL immunophenotype. A) Pro-B ALL: lymphoblasts are CD19, CD34, CD22, TdT and Cy CD79a positive and CD10 negative;
B) Pre-B ALL: lymphoblasts are CD22, CD34, CD19, TdT, cytoplasmic (Cy)CD79a, CD10 and Cy mμ positive;
C) Cortical/thymic TALL: Lymphoblasts are cyCD3, CD7, TdT, CD5, and CD1a positive.



Precursor B-cell ALL cells typically express CD10 (CALLA), CD19, and CD34 on their surface, along with nuclear terminal deoxynucleotide transferase (TdT).
Precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.


TdT is a protein expressed early in the development of pre-T and pre-B cells
CALLA (CD10) is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML. About 95% of all types of ALL (except Burkitt, which usually has an L3 morphology by the FAB classification) have elevated terminal deoxynucleotidyl transferase (TdT) expression. Cells observed as CD34+ and CD38- are of an undifferentiated, primitive form; i.e., they are multipotential hemopoietic stem cells.



About 95% of all types of ALL (except Burkitt, which usually has an L3 morphology by the FAB classification) have elevated terminal deoxynucleotidyl transferase (TdT) expression.

Terminal deoxynucleotidyl transferase (TdT), is a specialized DNA polymerase expressed in immature, pre-B, pre-T lymphoid cells, and acute lymphoblastic leukemia/lymphoma cells, while mature lymphoid cells are always TdT-negative.



B ALL blasts can be initially identified using SSC VS CD45 plot. These blast have low SSC (many times smaller than normal lympocytess), and dim to negative CD45. AML blast has higher SSC.

Hematogones are caraterized by very low side scatter (SSC) and dimmer expression of CD45 when compared to lymphocytes. They have variable ('smeared') expression of CD20; are positive for CD10 and partially for CD34.

Flow Diagnosis
B ALL: CD45 downregulated, CD10+, ( CD19+ ), surface light chains negative.

Pre B cells characteristically coexpress CD10 and CD19. Other B cll markers, CD20 and CD 23, are not expressed.

Expression of CD34 and TdT indicates immaturity and is characteristic in pre-B ALL.
Cytoplasmic expression of CD 79 confirms B cell lineage.

B-ALL is subdivided into:
Early pre B-ALL: CD10-, TdT+ ..... ( CD19+ ),
Pre B ALL: CD10+/-, ..... ( CD19+, HLA Dr+, cytoplasmic IgM+ )
Common ALL: CD10+, ..... ( CD19+ ), ((cytoplasmic IgM+, surface IgM-) ??)
Mature B ALL: CD10+, CD19+, CD20+, CD22+, surface IgM+



Pre B ALL: CALLA (CD10)+, TdT+, HLA-Dr+, CD34 75%, CD19+
CD10 89% CD13 5% CD19 100% CD20 24% CD22 69% CD33 31% CD34 76% CD45 (bright) 2% CD45 (moderate) 33% CD45 (dim) 36% CD45 (negative) 29% CD56 36% CD79a 88% CD117 0% cytoplasmic IgM 22% HLA Dr 98% TdT 91%



Genetics:
Some cytogenetic subtypes have a worse prognosis than others. These include:
• A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL.
• A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.

Some translocations are relatively favorable.
• Hyperdiploidy (>50 chromosomes) is a good prognostic factor.



CD34: Stem cells (also positive in angiosarcoma)

CD45 : All leukocytes (except Reed-Sternberg cells!)
CD33: Myeloid cells and precursors
CD13, CD33, CD117: Myeloid cells
CD14, CD64: Monocytic cells (positive in AML-M4 and AML-M5)

CD16, CD56: Natural killer cells
CD2, CD3, CD4, CD5, CD7, CD8: T cells

CD19, CD20, CD21, CD22 : B cells
CD10: Early pre-B cells (immature B cells)

CD23 and CD5 : Chronic lymphocytic leukemia/small lymphocytic lymphoma
CD23 negative and CD5 positive: Mantle cell lymphoma cells

CLL= 5+/23+, Mantle = 5+/23-. In addtion, CD200 is also a very useful differentiator between CLL (CD200+) and Mantle (CD200-).

Some T-ALL’s can be CD10 positive, so while this marker is “commonly” expressed on B-ALL’s it is not wholly restricted to this lineage.

CD 79 could be included and B cell could designated as mature and immature.
Mantle cell lymphoma is CD 5+.CD 23-, CD 79b+, FMC7 and cyclin D1 +

CD5 is a marker typically associated with T cells. However, it is briefly present in B cell development (it later disappears) – and it’s also present in CLL.



CD45 RO: Memory T cells
CD45 RA: Naive T cells

CD11c, CD25, CD103, CD123: Hairy cell leukemia cells

CD41, CD61: Megakaryocytes and platelets (positive in AML-M7)

CD1a, CD207: Langerhan cell histiocytosis cells

CD31: Endothelial cells (positive in angiosarcoma)

CD68: Histiocytes (positive in malignant fibrous histiocytosis)
CD99: Ewings sarcoma cells

CD99 is often overexpressed in T-ALL, it is also associated with Ewings

CD117: Gastrointestinal stromal tumor (GIST) cells, mast cells (positive in mastocytosis), myeloid cells



CD1a is also used as a cortical thymocyte marker in T Cells and is useful in classifying T-ALL.
Some T-ALL’s can be CD10 positive, so while this marker is “commonly” expressed on B-ALL’s it is not wholly restricted to this lineage.

 

Signs and symptoms

• Weakness or fatigue.
• Fever or night sweats.
• Bruises or bleeds easily (i.e., bleeding gums, purplish patches in the skin, or petechiae [flat, pinpoint spots under the skin]).
• Shortness of breath.
• Unexpected weight loss or anorexia.
• Pain in the bones or joints.
• Swollen lymph nodes, particularly lymph nodes in the neck, armpit, or groin, which are usually painless.
• Swelling or discomfort in the abdomen.
• Frequent infections.


Diagnosis

Patients with ALL may present with a variety of hematologic derangements ranging from pancytopenia to hyperleukocytosis. In addition to a history and physical, the initial workup should include:
• Complete blood count with differential.
• A chemistry panel (including uric acid, creatinine, blood urea nitrogen, potassium phosphate, calcium, bilirubin, and hepatic transaminases).
• Fibrinogen and tests of coagulation as a screen for disseminated intravascular coagulation.
• A careful screen for evidence of active infection.

A bone marrow biopsy and aspirate are routinely performed even in T-cell ALL to determine the extent of marrow involvement. Malignant cells should be sent for conventional cytogenetic studies, as detection of the Ph1 t(9;22), myc gene rearrangements (in Burkitt leukemia), and MLL gene rearrangements add important prognostic information. Flow cytometry should be performed to characterize expression of lineage-defining antigens and allow determination of the specific ALL subtype. In addition, for B-cell disease, the malignant cells should be analyzed using RT-PCR and FISH for evidence of the bcr-abl fusion gene. This last point is of utmost importance, as timely diagnosis of Ph1 ALL will significantly change the therapeutic approach.

Diagnostic confusion with AML, hairy cell leukemia, and malignant lymphoma is not uncommon. Proper diagnosis is crucial because of the difference in prognosis and treatment of ALL and AML. Immunophenotypic analysis is essential because leukemias that do not express myeloperoxidase include M0 AML, M7 AML, and ALL.

The examination of bone marrow aspirates and/or biopsy specimens should be done by an experienced oncologist, hematologist, hematopathologist, or general pathologist who is capable of interpreting conventional and specially stained specimens.

Prognosis and Survival

Factors associated with prognosis in patients with ALL include the following: • Age: Age, which is a significant factor in childhood ALL and AML, may be an important prognostic factor in adult ALL. In one study, overall, the prognosis was better in patients younger than 25 years; another study found a better prognosis in patients younger than 35 years. These findings may, in part, be related to the increased incidence of the Ph1 in older ALL patients, a subgroup associated with poor prognosis.

• CNS involvement: As in childhood ALL, adult patients with ALL are at risk of developing CNS involvement during the course of their disease. This is particularly true for patients with L3 (Burkitt) morphology. Both treatment and prognosis are influenced by this complication.

• Cellular morphology: Patients with L3 morphology showed improved outcomes, as evidenced in a completed Cancer and Leukemia Group B study (CLB-9251 [NCT00002494]), when treated according to specific treatment algorithms. This study found that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.

• Chromosomal abnormalities: Chromosomal abnormalities, including aneuploidy and translocations, have been described and may correlate with prognosis. In particular, patients with Ph1-positive t(9;22) ALL have a poor prognosis and represent more than 30% of adult cases. Bcr-abl-rearranged leukemias that do not demonstrate the classical Ph1 carry a poor prognosis that is similar to those that are Ph1-positive. Patients with Ph1-positive ALL are rarely cured with chemotherapy, although long-term survival is now being routinely reported when such patients are treated with combinations of chemotherapy and Bcr-abl tyrosine kinase inhibitors.

Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(4;11) and t(9;22), compared with patients with a normal karyotype, patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years.[13] In a multivariate analysis, karyotype was the most important predictor of disease-free survival.[Level of evidence: 3iiDii]

Late Effects of Treatment for Adult ALL

Long-term follow-up of 30 patients with ALL in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of ALL or AML younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.

Cellular Classification of Adult ALL

The following leukemic cell characteristics are important:
• Morphological features.
• Cytogenetic characteristics.
• Immunologic cell surface and biochemical markers.
• Cytochemistry.

In adults, French-American-British (FAB) L1 morphology (more mature-appearing lymphoblasts) is present in fewer than 50% of patients, and L2 morphology (more immature and pleomorphic) predominates.
L3 (Burkitt) acute lymphoblastic leukemia (ALL) is much less common than the other two FAB subtypes. It is characterized by blasts with cytoplasmic vacuolizations and surface expression of immunoglobulin, and the bone marrow often has an appearance described as a “starry sky” owing to the presence of numerous apoptotic cells. L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).

Some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia chromosome (Ph1). The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL. In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).

Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction for the bcr-abl fusion gene because many patients have a different fusion protein from the one found in CML (p190 vs. p210).

Using heteroantisera and monoclonal antibodies, ALL cells can be divided into several subtypes

Frequency of Acute Lymphoblastic Leukemia (ALL) Cell Subtypes

Cell Subtype Approximate Frequency
Early B-cell lineage 80%
T cells 10%–15%
B cells with surface immunoglobulins <5%

About 95% of all types of ALL (except Burkitt, which usually has an L3 morphology by the FAB classification) have elevated terminal deoxynucleotidyl transferase (TdT) expression. This elevation is extremely useful in diagnosis; if concentrations of the enzyme are not elevated, the diagnosis of ALL is suspect. However, 20% of cases of AML may express TdT; therefore, its usefulness as a lineage marker is limited.
Because Burkitt leukemias are managed according to different treatment algorithms, it is important to specifically identify these cases prospectively by their L3 morphology, absence of TdT, and expression of surface immunoglobulin. Patients with Burkitt leukemias will typically have one of the following three chromosomal translocations:
• t(8;14). • t(2;8). • t(8;22).

 

Stage Information for Adult ALL

There is no clear-cut staging system for this disease. This disease is classified as untreated, in remission, or recurrent.

Untreated Adult ALL
For a newly diagnosed patient with no prior treatment, untreated adult acute lymphoblastic leukemia (ALL) is defined by the following:
• Abnormal white blood cell count and differential.
• Abnormal hematocrit/hemoglobin and platelet counts.
• Abnormal bone marrow with more than 5% blasts.
• Signs and symptoms of the disease.

Adult ALL in Remission
A patient who has received remission-induction treatment of ALL is in remission if all of the following criteria are met:
• Bone marrow is normocellular with no more than 5% blasts.
• There are no signs or symptoms of the disease.
• There are no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.
• All of the following laboratory values are within normal limits:
        • White blood cell count and differential.
        • Hematocrit/hemoglobin level.
        • Platelet count.

 

 

Treatment Option Overview for ALL

Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease and the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS).
The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic therapy) and, in some cases, cranial radiation therapy.

Treatment is divided into the following three phases:
• Remission induction.
• CNS prophylaxis.
• Postremission (also called remission continuation or maintenance).

The average length of treatment for ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. Younger adults with ALL may be eligible for selected clinical trials for childhood ALL. (Refer to the Adolescents and Young Adults With ALL section in the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for more information.)

Entry into a clinical trial is highly desirable to assure adequate patient treatment and maximal information retrieval from the treatment of this highly responsive, but usually fatal, disease.

Standard Treatment Options for Adult Acute Lymphoblastic Leukemia (ALL)


Disease Status Standard Treatment Options
Untreated ALL Remission induction therapy
CNS prophylaxis therapy
ALL in remission Postremission therapy
CNS prophylaxis therapy
Recurrent ALL Reinduction chemotherapy and/or blinatumomab
Palliative radiation therapy
Dasatinib

 

Treatment for Untreated Adult ALL


Standard Treatment Options for Untreated Adult ALL
1.Remission induction therapy, including the following:
• Combination chemotherapy.
• Imatinib mesylate (for patients with Philadelphia chromosome [Ph1]-positive ALL).
• Imatinib mesylate combined with combination chemotherapy (for patients with Ph1-positive ALL)
• Supportive care.

2.Central nervous system (CNS) prophylaxis therapy, including the following:
• Cranial radiation therapy plus intrathecal (IT) methotrexate.
• High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
• IT chemotherapy alone.

SUMMARY:
# Combination chemotherapy with prednisone, vincristine, and an anthracycline with or without asparaginase.
# In patients with Ph1-positive ALL, add Bcr-abl tyrosine kinase inhibitors to combination chemotherapy with prednisone, vincristine, and an anthracycline, without asparaginase.

#Supportive care
• Prophylactic platelet transfusions (pooled platelet concentrates) at a level of 10,000/mm3 - 20,000/mm3. The incidence of platelet alloimmunization was similar among groups randomly assigned.
• Empiric broad-spectrum antimicrobial therapy for febrile patients who are profoundly neutropenic.
Careful instruction in personal hygiene and dental care and in recognizing early signs of infection.
• White blood cell transfusions in selected patients with aplastic marrow and serious infections that are not responding to antibiotics.
• Prophylactic oral antibiotics in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 wk), though further studies are necessary.
• Serial surveillance cultures may be helpful in detecting the presence or acquisition of resistant organisms.
• The use of myeloid growth factors during remission-induction therapy appears to decrease the time to hematopoietic reconstitution.

 



1. Remission induction therapy

Sixty percent to 80% of adults with ALL usually achieve a complete remission status following appropriate induction therapy. Appropriate initial treatment, usually consisting of a regimen that includes the combination of vincristine, prednisone, and an anthracycline, with or without asparaginase, results in a complete response rate of up to 80%. In patients with Ph1-positive ALL, the remission rate is generally greater than 90% when standard induction regimens are combined with Bcr-abl tyrosine kinase inhibitors. In the largest study published to date of Ph1-positive ALL patients, overall survival (OS) for 1,913 adult ALL patients was 39% at 5 years.

Patients who experience a relapse after remission usually die within 1 year, even if a second complete remission is achieved. If there are appropriate available donors and if the patient is younger than 55 years, bone marrow transplantation may be a consideration in the management of this disease. Transplant centers performing five or fewer transplants annually usually have poorer results than larger centers. If allogeneic transplant is considered, a recommendation is that transfusions with blood products from a potential donor be avoided, if possible.

Combination chemotherapy
Most current induction regimens for patients with adult ALL include combination chemotherapy with prednisone, vincristine, and an anthracycline. Some regimens, including those used in a Cancer and Leukemia Group B (CALGB) study (CLB-8811), also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%.

■ Imatinib mesylate (Bcr-abl tyrosine kinase inhibitor)
Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in Ph1-positive ALL.[Level of evidence: 3iiiDiv] More commonly, particularly in younger patients, imatinib is incorporated into combination chemotherapy regimens. There are several published single-arm studies in which the complete response rate and survival are compared with historical controls.

Evidence (Imatinib mesylate):
Several studies have suggested that the addition of imatinib to conventional combination chemotherapy induction regimens results in complete response rates, event-free survival rates, and OS rates that are higher than those in historical controls. At the present time, no conclusions can be drawn regarding the optimal imatinib dose or schedule.
DOSAGE & INDICATIONS: GoTo Bcr-abl tyrosine kinase inhibitors

Supportive care
Since myelosuppression is an anticipated consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support and for the treatment of infectious complications.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions, when appropriate.

Evidence (Supportive care):
1.Randomized clinical trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than at a level of 20,000/mm3.
2.The incidence of platelet alloimmunization was similar among groups randomly assigned to receive one of the following from random donors:
• Pooled platelet concentrates.
• Filtered, pooled platelet concentrates.
• Ultraviolet B-irradiated, pooled platelet concentrates.
• Filtered platelets obtained by apheresis.

Empiric broad-spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. Careful instruction in personal hygiene and dental care and in recognizing early signs of infection are appropriate for all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization, are not routinely indicated but may benefit transplant patients.

Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that are not responding to antibiotics.[27] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 wk), though further studies are necessary.[28] Serial surveillance cultures may be helpful in detecting the presence or acquisition of resistant organisms in these patients. As suggested in a CALGB study (CLB-9111), the use of myeloid growth factors during remission-induction therapy appears to decrease the time to hematopoietic reconstitution.

2. CNS prophylaxis therapy
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.

Special Considerations for B-Cell and T-Cell Adult ALL
Two additional subtypes of adult ALL require special consideration. B-cell ALL, which expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22), is not usually cured with typical ALL regimens. Aggressive brief-duration high-intensity regimens, including those previously used in CLB-9251 (NCT00002494), that are similar to those used in aggressive non-Hodgkin lymphoma have shown high response rates and cure rates (75% complete response; 40% failure-free survival). Similarly, T-cell ALL, including lymphoblastic lymphoma, has shown high cure rates when treated with cyclophosphamide-containing regimens.

Whenever possible, patients with B-cell or T-cell ALL should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma and Lymphoblastic lymphoma sections in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

 

 


Treatment for Adult ALL in Remission


Standard Treatment Options for Adult ALL in Remission
1. Postremission therapy, including the following:
• Chemotherapy.
• Ongoing treatment with a Bcr-abl tyrosine kinase inhibitor, such as imatinib, nilotinib, or dasatinib.
• Autologous or allogeneic bone marrow transplant (BMT).

2. Central nervous system (CNS) prophylaxis therapy, including the following:
• Cranial radiation therapy plus intrathecal (IT) methotrexate.
• High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
• IT chemotherapy alone.


Good prognoses were found for patients with T-cell lineage ALL,
Poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11).
Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.

SUMMARY:
Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:
• Longer-term therapy at lower doses (maintenance therapy).
• Allogeneic bone marrow transplant.
Because the optimal postremission therapy for patients with ALL is still unclear, a consideration is participation in clinical trials.

Aggressive postremission chemotherapy for adult ALL have confirmed a long-term disease-free survival (DFS) rate of approximately 40%.

Allogeneic BMT results in the lowest incidence of leukemic relapse, even when compared with a BMT from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in DFS in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.

The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high-risk or Ph1-positive ALL. This was confirmed in the ECOG-2993 (NCT01505699) study.
The results of the International ALL Trial (ECOG-2993) suggest the existence of a graft-versus-leukemia effect for adult Ph1-negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long-term survival for patients with standard-risk adult ALL in first remission. The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.

 



1. Postremission therapy

Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:
• Longer-term therapy at lower doses (maintenance therapy).
• Allogeneic bone marrow transplant.

Because the optimal postremission therapy for patients with ALL is still unclear, a consideration is participation in clinical trials.

Evidence (Chemotherapy):
1.Several trials, including studies from the Cancer and Leukemia Group B (CLB-8811) and the completed European Cooperative Oncology Group (ECOG-2993 [NCT00002514]), of aggressive postremission chemotherapy for adult ALL have confirmed a long-term disease-free survival (DFS) rate of approximately 40%.
• In two series, especially good prognoses were found for patients with T-cell lineage ALL, with DFS rates of 50% to 70% for patients receiving postremission therapy.
• These series represent a significant improvement in DFS rates over previous, less intensive chemotherapeutic approaches.

2.In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11).

Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications are necessary. Studies in which continuation or maintenance chemotherapy was eliminated had outcomes inferior to those with extended treatment durations.[8,9] Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.

Evidence (Allogeneic and autologous BMT):
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a BMT from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in DFS in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.

1.The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high-risk or Ph1-positive ALL. This was confirmed in the ECOG-2993 (NCT01505699) study.
•The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decade.
•The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.

2.Following on the results of earlier studies, the International ALL Trial (ECOG-2993) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively; patients were accrued from 1993 to 2006. Patients with Ph1-negative ALL between the ages of 15 years and 59 years received identical multiagent induction therapy resembling previously published regimens. Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation therapy. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS); event-free survival, relapse rate, and nonrelapse mortality were secondary outcomes. A total of 1,929 patients were registered and stratified according to age, white blood cell (WBC) count, and time to remission. High-risk patients were defined as those having a high WBC count at presentation or those older than 35 years.
a.Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 had an HLA-identical sibling, 310 of whom underwent an alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT.
b. By donor-to-no-donor analysis, standard-risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01).
c.In a subgroup analysis, the advantage for patients with standard-risk ALL who had donors remained significant (OS = 62% vs. 52%; P = .02).
•For patients with high-risk disease (older than 35 y or high WBC count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2).
•Relapse rates were significantly lower (P < .00005) for both standard- and high-risk patients with HLA-matched donors.
d.In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-y OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03).
e.The results of this trial suggest the existence of a graft-versus-leukemia effect for adult Ph1-negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long-term survival for patients with standard-risk adult ALL in first remission.[Level of evidence: 2A]
f.The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[Level of evidence: 2A]

The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, it is reserved for patients in second remission or beyond. The dose of total-body radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[Level of evidence: 3iiB]

Evidence (B-cell ALL):
Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged DFS for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).

1.Retrospectively reviewing three sequential cooperative group trials from Germany, one group of investigators found the following:[19] •A marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in two subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months.

2. CNS prophylaxis therapy

The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease. Some authors have suggested that there is a subgroup of patients at low risk for CNS relapse for whom CNS prophylaxis may not be necessary. However, this concept has not been tested prospectively.

Aggressive CNS prophylaxis remains a prominent component of treatment. This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin and L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype, but unusual cytogenetic features, were not cured with this approach. A WBC count of less than 50,000 per microliter predicted improved leukemia-free survival in a univariate analysis.

 

 

Treatment for Recurrent Adult ALL


Standard Treatment Options for Recurrent Adult ALL
1.Reinduction chemotherapy and/or blinatumomab followed by allogeneic bone marrow transplantation (alloBMT).
2.Palliative radiation therapy (for patients with symptomatic recurrence).
3.Dasatinib (for patients with Philadelphia chromosome [Ph1]-positive ALL).

SUMMARY:
1.Reinduction chemotherapy and/or blinatumomab followed by allogeneic bone marrow transplantation (alloBMT).
Blinatumomab should be considered as an option for reinduction therapy for patients with primary refractory disease, which is refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation.
2.Palliative radiation therapy (for patients with symptomatic recurrence).
3.Dasatinib (for patients with Philadelphia chromosome [Ph1]-positive ALL).

 



1. Reinduction chemotherapy

Patients with ALL who experience a relapse following chemotherapy and maintenance therapy are unlikely to be cured by further chemotherapy alone. These patients should be considered for reinduction chemotherapy followed by alloBMT.

Blinatumomab
Evidence (blinatumomab):
1.A randomized phase III study of blinatumomab versus one of four standard reinduction regimens was conducted in patients with primary refractory disease, which was refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation. The four regimens included the following:
fludarabine, high-dose cytosine arabinoside, and granulocyte colony-stimulating factor with or without anthracycline;
a high-dose cytosine arabinoside–based regimen;
a high-dose methotrexate-based regimen; or
a clofarabine-based regimen.
• Remission rates were 43.9% for the blinatumomab-treated group versus 24.6% in the standard-treatment group (odds ratio, 2.40; 95% confidence interval [CI], 1.51–3.80).
• Overall survival was superior in the blinatumomab-treated group (7.7 mo vs. 4.0 mo in the standard-treatment group) with a hazard ratio of .71 (95% CI, 0.55–0.93), favoring blinatumomab.
• Adverse events occurred at similar rates in both groups, and the only unique side effect of blinatumomab was cytokine-release syndrome, which was seen in 4.9% of patients.

Blinatumomab should be considered as an option for reinduction therapy for patients with primary refractory disease, which is refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation.[Level of evidence: 1iiA]

2. Palliative radiation therapy

Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.

3. Dasatinib

Patients with Ph1-positive ALL will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR-ABL mutations, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leukemia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL.

Evidence (Dasatinib):
1. In one study, ten patients were treated with dose-escalated dasatinib. Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood cell counts), three of whom had a complete cytogenetic response.
• The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%).
• Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib.

Treatment Options Under Clinical Evaluation for Recurrent Adult ALL
Patients for whom an HLA-matched donor is not available are excellent candidates for enrollment in clinical trials that are studying the following:
1. Autologous transplantation.
2. Immunomodulation.
3. Chimeric antigen receptor (CAR) T-cell therapy.
4. Novel chemotherapeutic or biological agents.