Acute lymphoblastic leukemia C91.00

ALL is characterized as a malignant clonal neoplasia of immature lymphoid cells of hematopoiesis in bone marrow and blood. (Note: Immature cell here refers to a cytological term and refers to the morphology of the leukemic cells. Acute refers to the course of the disease. In general, both terms are accurate, as immature ALL is usually acute). All other lymphoid organs such as lymph nodes, spleen as well as many non-lymphoid organs such as liver, lungs, CNS (meningiosis leukaemica), skin (leukaemia cutis), bones, may also be affected. With regard to hematopoiesis, poorly differentiated or undifferentiated leukemic blasts displace the normal hematopoietic bone marrow. The hematological consequence is cytopenias of all three cell series (anemia, thrombocytopenia, granulocytopenia). If organs are affected, organ-typical symptoms can be found (e.g. in the skin: specific skin infiltrates, non-specific rejections due to immunosuppression, exanthema in the wake of therapy, see also Rash of lymphocyte recovery).

Basically, ALL is classified together with lymphoblastic lymphomas as precursor lymphoid neoplasm of B- or T-cell type (WHO classification 2016).

By definition, a clonal neoplasm with bone marrow involvement < 25% = is referred to as lymphoblastic lymphoma, and with bone marrow involvement > 25% is referred to as acute lymphoblastic leukemia (ALL).

Table WHO classification of ALL 2016

Precursor lymphoid neoplasms

B lymphoblastic leukaemia/lymphoma, NOS (not otherwise specified)

B lymphoblastic leukaemia/lymphoma, with recurrent genetic abnormalities

B lymphoblastic leukaemia/lymphoma, with t(9;22)(q34;q11.2); BCR-ABL1

B lymphoblastic leukaemia/lymphoma, with t(v;11q23); KMT2A rearranged

B lymphoblastic leukaemia/lymphoma, with t(12;21)(p13;q22); ETV6-RUNX1

B lymphoblastic leukaemia/lymphoma, with hyperdiploidy

B lymphoblastic leukaemia/lymphoma, with hypodiploidy

B lymphoblastic leukaemia/lymphoma, with t(5;14)(q31;q32);IL3-IGH

B lymphoblastic leukaemia/lymphoma, with t(1;19)(q23;p13.3); TCF3-PBX1

B lymphoblastic leukemia/lymphoma, with BCR-ABL1-like

B lymphoblastic leukemia/lymphoma, with iAMP21

T-lymphoblastic leukemia/lymphoma

Early T-cell precursor lymphoblastic leukemia

Provisional entity: Natural Killer (NK) cell lymphoblastic leukemia/lymphoma

Mature B-cell neoplasms

Burkitt's lymphoma (only mature cell "Burkitt's" B-ALL is classified here, which is not listed as a separate entity)

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Immunological subclassification of ALL in the GMALL studies

B- lines ALL

Immunophenotyping: HLA-DR+, TdT+, CD19+ u./o. cyCD79a+ u./o. cyCD22+/ Incidence: 76%.

B-precursor ALL

• Pro-B
• immunophenotyping: CD10-/ incidence: 11%/ typical cyto/molecular genetics: t(4v;11); KMT2A rearrangements
• c- (common)
• Immunophenotyping: CD10+/ incidence: 49%/ typical cyto/molecular genetics: t(9;22); BCR-ABL; IKZF1*
• Pre-B
• Immunophenotyping: cyIgM+/ incidence: 12%/ typical cyto/molecular genetics: t(1;19); TCF3-PBX1; t(9;22); BCR-ABL; IKZF1*

Mature B-ALL

• immunophenotyping: sIg+/ incidence: 4%/ typical cyto/molecular genetics: t(8;14); MYC rearrangements

T- lineage ALL

immunophenotyping: TdT+, cyCD3+, CD7+/ incidence: 24%

• "Early" T-ALL - immunophenotyping: CD2-, sCD3-, CD1a/ incidence: 6%/ typical cyto/molecular genetics: PTEN*, N/K-RAS*.
• "Thymic" T-ALL- immunophenotyping: sCD3±, CD1a+/ incidence: 12%/ typical cyto/molecular genetics: NOTCH1/FBXW7*.
• "Mature" T-ALL- immunophenotyping: sCD3+, CD1a-/ incidence: 6%.

Overall incidence: 1.1/100,000/year. M:w=1.4:1.0.

Uncontrolled proliferation of early lymphoid progenitor cells in the bone marrow. Degeneration can occur at different levels of lymphoid cell maturation. Thus, leukemic cells in subsets of ALL exhibit different phenotypic features, e.g. surface markers, which are related to the maturation stage and also to the clinical manifestation of the disease.

More than 60% of adult ALL patients show cytogenetic aberrations, which are often also characteristic of certain phenotypic and clinical manifestations and in some cases have prognostic significance. The affected genes or their gene products are proteins involved in signal transduction, transcription regulation, cell cycle control and/or the regulation of apoptosis. The alteration of individual genes usually has complex consequences for the expression of downstream genes and their regulatory network. It can be assumed that several genetic aberrations are required to trigger malignant degeneration of lymphoid progenitor cells. As a consequence, there are disturbances in differentiation, increase in proliferative functions, or loss of mechanisms that induce apoptosis. Ultimately, these changes confer a survival advantage to the malignant clone and lead to a differentiation block at a specific maturation level, analogous to normal lymphoid progenitor cells.

Thus, translocation t(9;22) (Philadelphia chromosome, Ph) is associated with the formation of the BCR-ABL fusion gene. As a consequence, an encoded protein with aberrant tyrosine kinase activity is causally associated with the development of Ph/BCR-ABL-positive ALL. New molecular genetic techniques have already succeeded in identifying 23 subtypes within B-precursor ALL (Gu Z et al. 2019). Their prognostic significance is currently not always clarified in individual cases. In BCR-ABL-like ALL, potential therapeutic targets can already be identified.

Suspected endogenous and exogenous risk factors are:

• Genetic factors: congenital defects of DNA repair mechanisms (example: ataxia teleangiectasia). In patients with trisomy 21, the genetic defect increases the risk of acute leukemia 18-fold compared to comparison groups.
• Ionizing radiation (e.g. Hiroshima, 32P-therapy after polycythemia vera)
• Exposure to myelotoxic chemicals, such as benzene (BK-Nr.1303!), chloramphenicol, etc.
• ALL as sequelae after chemotherapy, e.g. with alkylants, epipodophyllotoxins
• Viruses: HTLV1 (or 2) viruses cause an endemic (southern Japan, Caribbean) special form of T-All (C91.5).

The absolute peak incidence is in children under 5 years of age (5.3/100,000). Thereafter, the incidence decreases continuously. In patients over 50 years of age, it slowly increases again and reaches a second frequency peak at the age of > 80 years (2.3/100,000).

The clinical picture of ALL is characterized by proliferation and accumulation of malignant degenerated immature lymphoid blasts in bone marrow, blood, lymphoid and non-lymphoid tissues.

Symptoms of hematologic insufficiency include:

• Anemia: pale skin and mucous membranes, tachycardia, dyspnea, dizziness, decreased performance.
• Granulocytopenia in the presence of leukopenia or hyperleukocytosis or normally high
• total leukocyte count in the blood count: fever, tendency to infection
• Thrombocytopenia: bleeding tendency, hematoma tendency, petechiae.

One third of patients suffer from infections or bleeding at diagnosis. Almost 60% have enlarged lymph nodes . Splenomegaly is equally common. A mediastinal tumor is found in 14% of cases of ALL overall, but in 60% of patients with T-ALL. Other extramedullary organ involvement is present in 9% of cases of ALL.

CNS involvement is usually diagnosed during a routine CSF examination; however, symptoms may include headache, vomiting, lethargy, neck stiffness, nerve deficits (especially cranial nerves), and paraplegic symptoms if the spinal cord is involved.

Skin symptoms(leukaemia cutis) are rare. The incidence is unknown. Often no distinction is made between AML and ALL. They are divided into specific (leukemic infiltrates of the skin) and non-specific (skin changes in the context of immunosuppression).

Leukocytosis is found in 60% of ALL patients. The absence of leukocytosis, anemia, thrombocytopenia or even the absence of blasts in the blood do not exclude ALL. As a rule, the symptoms of the disease develop within days and are accompanied by a rapid loss of physical performance.

The following examinations are considered necessary:

• Medical history and physical examination
• General condition and evaluation of comorbidities
• ECG and echocardiography
• Laboratory: blood count, differential blood count, clinical chemistry including coagulation and urinalysis
• HLA typing if necessary (in case of potential indication for stem cell transplantation)
• Virology: Infectious disease tests including hepatitis B,C and HIV serology
• Pregnancy test
• Lumbar puncture with cytological CSF diagnostics and intrathecal therapy
• Immunophenotyping (bone marrow)
• Molecular genetics BCR-ABL, KMT2A-AFF1
• Cytogenetics and molecular cytogenetics for the detection of a translocation t(9;22); t(4;11), etc.

• Note: Education on fertility preserving measures and need for anticonception. In all patients the possibility of biomaterial preservation should be sought, e.g. in the context of the study group.

  
  

X-ray thorax

Sonography (abdomen, neck organs, lymph nodes)

CT: thorax and abdomen; further targeted examinations depending on symptoms)

Immunological and morphological identification of lymphoid blasts allows differentiation from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia, lymphoid blast relapse in CML or other forms of chronic and acute leukemias as well as from reactive lymphocytoses, e.g. in infectious mononucleosis. ALL is differentiated from T- or B-lymphoblastic lymphomas on the basis of the proportion of blasts in the bone marrow.

In approximately 29% of patients, typical ALL blasts show co-expression of myeloid surface markers such as CD13, CD33 (>20%). Certain subgroups of ALL are associated with a higher incidence of myeloid co-expression, e.g. "early" T-ALL, pro-B-ALL, Ph/BCR-ABL-positive ALL. Myeloid coexpression is not prognostically relevant. Patients are treated according to the relevant ALL protocols.

The therapy standard is curative. The standard is established by the studies and expert recommendations of GMALL (German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia). Long-term survival rates in adults have improved over the last decades and with current therapy concepts for patients up to the age of 55 years are around 60-70% with a large variation depending on age and risk group.

The therapy of ALL is divided into several phases: Induction, consolidation and maintenance therapy. The goal of induction therapy is the induction of a complete remission (CR) of the disease. The achievement of a CR is a prerequisite for long-term survival or cure of the disease. The therapy phases consolidation and maintenance therapy serve to maintain the complete remission and are summarized under the term post-remission therapy.

Pre-phase therapy: Pre-phase therapy (dexamethasone, cyclophosphamide) should be given to all patients to avoid tumor lysis syndrome. Even in patients with hyperleukocytosis, pre-phase therapy is generally sufficient for gentle cell reduction.

Induction therapy in patients under 55 years of age with ALL or LBL: Standard drugs for the actual induction therapy are vincristine and dexamethasone in combination with an anthracycline derivative (usually dauno/doxorubicin). In addition, asparaginase is used in induction therapy; the substance is specifically effective in ALL and differs from other cytostatics in terms of mechanism of action, resistance and side effect spectrum.

After induction phase I, remission control with MRD determination is performed. If a complete remission (blast percentage <5%) is not achieved according to cytological findings, the patient must be assigned to the high-risk group. In case of borderline cytological findings, the MRD result should be awaited for the final classification. The sole detection of CD10/CD19-positive cells in the flow cytometry can neither be interpreted as an unequivocal blast detection nor as an MRD detection, since especially in the regenerating bone marrow they can also be hematogones. If extramedullary involvement is initially detected, it should be followed up by appropriate imaging and included in the overall assessment of remission.

Induction phase II involves the addition of further drugs - cyclophosphamide, cytosine arabinoside, 6-mercaptopurine and intrathecal prophylaxis with methotrexate. Usually, induction phase II again causes a significant decrease in minimal residual disease (Gökbuget N et al (2012).

Consolidation therapy: The implementation of an intensive consolidation therapy is standard in the therapy of ALL. Very different concepts exist internationally for consolidation therapy and the efficacy of individual elements can hardly be proven individually. However, the available data suggest that cyclic consolidation therapy with changing substances and especially the intensive use of high-dose methotrexate, high-dose cytarabine, increased dose intensity for asparaginase as well as the repetition of induction therapy (reinduction) is beneficial. It is essential that the therapeutic blocks in consolidation therapy are administered as promptly as possible.

Maintenance therapy: For all ALL patients (except for patients with mature B-ALL/Burkitt's leukemia) who do not receive SCT, maintenance therapy is the standard of care after completion of the consolidation and intensification cycles. All studies in which maintenance therapy was omitted have had significantly less favorable overall results. In maintenance therapy, methotrexate is administered orally weekly and mercaptopurine daily. Dosages are adjusted to blood counts.

Stem cell transplantation (SCT): Allogeneic SCT is an essential component of post-remission therapy in adult ALL. Both family and unrelated donors are used, with twice as many unrelated as family donor transplants now being performed due to excellent donor registries. The results are comparable. Autologous SCT is now performed only in rare individual cases after further consolidation therapy. The indication for SZT in first remission varies internationally. The majority of study groups follow a risk-adapted indication for SZT in first remission (Giebel S et al. 2019). In all patients with high-risk features, transplantation is targeted in first CR. Standard-risk patients are not targeted for transplantation in first remission, as they achieve survival rates above 60% even with conventional chemotherapy. The indication for SCT in standard risk patients is molecular relapse or treatment failure.

CNS prophylaxis: The implementation of effective prophylaxis of CNS recurrences is of critical importance in the treatment of ALL. Risk factors for the development of CNS relapse include T-ALL, mature B-ALL/Burkitt's leukemia, and a high leukocyte count at diagnosis. Treatment modalities include intrathecal therapy with methotrexate, with a triple combination (methotrexate, cytarabine, steroid), systemic high-dose therapy with methotrexate and/or cytarabine, and whole-brain radiation (24 Gy). With initial CNS involvement, intensified intrathecal therapy with 2- to 3-times weekly administrations until blast clearance and 1-2 additional consolidation administrations must be performed. In case of frequent intrathecal instillation of methotrexate, a leucovorin rescue should be performed for mucositis prophylaxis.

Therapy of Ph/BCR-ABL-positive ALL: The Philadelphia (Ph) chromosome or corresponding fusion transcript BCR-ABL is the most common recurrent aberration in ALL, with an incidence of 30-50% within B-precursor ALL. The incidence increases with age. The use of tyrosine kinase (TK) inhibitors, particularly imatinib, has significantly improved the prognosis of this subgroup (Ravandi F 2019).In younger patients, imatinib is used in combination with chemotherapy . Remission rates of over 90% are achieved; molecular remission rates are over 50%.

Because of the development of resistance and relapse with chemotherapy in combination with TKIs, stem cell transplantation appears to remain the only option for achieving long-term remission in Ph+ ALL. Further improvement seems possible with the administration of imatinib after transplantation.

In older patients with Ph+ ALL, the approach of induction therapy with imatinib as monotherapy has been predominantly tested in trials. This therapy, which can often be performed on an outpatient basis, achieves a CR in 90% of patients and is thus superior to intensive induction chemotherapy in combination with imatinib (Ottmann OG et al. (2007).

Crucial for therapy management is the quantitative measurement of MRD and, in case of MRD detection, the measurement of resistance-inducing mutations with the highest possible sensitivity.

Recurrence: The probability of recurrence is highest in the first two years after achieving CR. Early relapses with primary remission duration less than 18 months and refractory relapses are prognostically unfavorable. The main goal in the management of relapsed patients is the achievement of a complete remission and subsequent stem cell transplantation, if the patients are individually suitable for this. Achieving CR is a prerequisite for stabilization of the patient with hematologic remission and usually for subsequent transplantation. Molecular remission should be sought if possible, although the prognostic significance of MRD after relapse is less clear than in first-line therapy. Overall survival of ALL after relapse is <10% in published studies (Gökbuget N et al 2012). Increasingly, consistent MRD determination is successful in identifying the increase in leukemia burden prior to the occurrence of cytologic relapse and initiating treatment in the MRD setting. In the treatment of early relapses and refractory relapses of B-precursor ALL, standard chemotherapies produce significantly worse results than the new immunotherapies with blinatumomab or inotuzumab (Kantarjian HM et al. 2016).

CAR-T:Promising data exist for the use of genetically engineered T cells. The so-called chimeric antigen receptor T cells (CAR-T) are engineered ex-vivo from patient T cells with an antigen receptor against leukemia cell surface markers and various signal transduction elements (Majzner RG et al. 2019). Chimeric antigen receptor-modified T cell (CART) therapy has significantly improved the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) (Yang M et al 2020)

Comment: Lymphoblastic lymphoma (bone marrow involvement < 25%) can be treated very successfully with adapted regimens for ALL.

Prognostic factors are generally accepted in adult ALL (Beldjord K et al 2014; Roberts KG 2017) . However, there are some differences in the risk stratification of the individual study groups and especially with regard to the therapeutic consequences.

Riskoc groups (unfavourable prognostic factors in adult ALL):

High leukocyte count > 30,000/µl in B precursor ALL.

subtype pro B, early T-ALL, mature T-ALL

Late CR > 3 Wo (after induction II)

Cytogenetic/molecular aberrations: t(9;22) - BCR-ABL ; t(4;11) - KMT2A-AFF1

Minimal residual disease

MRD level above 10-4 after early consolidation

MRD increase above 10-4 after prior molecular CR.

The listed risk factors define a standard group (without unfavorable prognostic factors) and a high-risk group (at least one unfavorable prognostic factor).

1. Beldjord K et al. (2014) Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood 123:3739-3749.
2. Giebel S et al. (2019) Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 54:798-809
3. Gökbuget N et al. (2012) Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 120:2032-2041.
4. Gökbuget N et al. (2012) Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood 120:1868-1876.
5. Gu Z et al (2019) PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet 51:296-30.
6. Kantarjian HM et al (2016): Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute lymphoblastic leukemia: results from 2 phase 2 studies. Cancer 122:2178-2185.
7. Majzner RG et al (2019) Clinical lessons learned from the first leg of the CAR T cell journey. Nat Med 25:1341-1355.
8. Ottmann OG et al (2007) Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
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10. Roberts KG (2017) The biology of Philadelphia chromosome-like ALL. Best Pract Res Clin Haematol 30:212-221.
11. van Dongen JJ et al. (2015) Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 125:3996-4009.
12. WHO classification (2017) WHO Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues" International Agency for Research of Cancer , Revised 4th Edition, Lyon.
13. Yang M et al. (2020) Chimeric antigen receptor-modified T-cell therapy for bone marrow and skin relapse Philadelphia chromosome-like acute lymphoblastic leukemia: A case report. Medicine (Baltimore) 99:e18639.