Acute Lymphoblastic Lymphoma
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This document provides a summary of acute lymphoblastic leukemia (ALL) including its epidemiology, etiology, classification, clinical features, diagnosis, treatment approaches, and genetic subtypes. It notes that ALL is most common in children and accounts for 30% of all childhood cancers. The document discusses immunophenotyping and cytogenetics in classifying ALL and identifies several genetic subtypes associated with different prognoses like the Philadelphia chromosome. Standard treatment involves induction, consolidation, and maintenance chemotherapy with central nervous system prophylaxis.
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Acute Lymphoblastic Lymphoma
- 1. Target Audience : Oncology Fellows, Oncology physicians, Oncologists Archer Board Review Courses www.Ccsworkshop.com ACUTE LYMPHOBLASTIC LEUKEMIA
- 7. ALL – CLASSIFICATION FAB
- 8. ALL – CLASSIFICATION FAB
- 12. ALL CYTOGENETICS AND FISH – GENETIC SUBTYPES OF ALL
- 13. ALL IN ADULTS CYTOGENETIC AND MOLECULAR ABNORMALITIES
- 14. MOLECULAR AND CYTOGENETIC SUBTYPES OF B-LINEAGE ALL *Most common in infant leukemia (mixed AML-ALL). Bassan R, et al. Crit Rev Oncol Hematol. 2004;50:223-261. Subtype ( Cytogenetics) Karyotype Childhood Frequency, % Adult Frequency, % Childhood EFS, % Adult EFS, % Hyperdiploidy > 50 chr 25 5 80-90 40-50 TEL/AML1 t(12;21) 25 3 85-90 ? MYC t(8;14) 2 5 75-85 60-70 bcr/abl t(9;22) 5 33 20-40 < 10 MLL/AF4* t(4;11) 3 6 30 15
- 15. MOLECULAR AND CYTOGENETIC SUBTYPES T-CELL LINEAGE ALL Armstrong SA, Look AT. J Clin Oncol. 2005;26:6306-6315. Graux C, et al. Leukemia. 2006;20:1496-1510. Subtype (Cytogenetics) Karyotype Childhood Frequency, % Adult Frequency, % Childhood EFS, % Adult EFS, % HOX11 expression -- 3 33 90 60 NOTCH1 mutations -- 50 50 90 -- TCR t(14q11) 15 25 70 60 MLL-ENL t(11;19) 2 2 95 --
- 16. ALL CYTOGENETICS – GENETIC SUBTYPES OF ALL Cytogenetic abnomality Genes Adult Childhood Type Prognosis t(9:22) BCR/ABL 30% 3% Common / Pre B-ALL (CD10+) Azurophilic granules Unfavorable t(v;11q23) or t(4,11) MLL 5% Topoismomerase related 3% Infants with organomegaly Pro B-ALL CD10- Unfavorable - High rate of early treatment failure t(8,14) MYC/IGH 5% 2% Mature B-Cell, FAB L3 t(1,14) TAL1/TCR 3% T-cell disease t(1;19) PBX/E2A 3% 6% (25% Pre B-ALL) Previously unfavorable now normal prognosis with aggressive therapy. t(12;21) TEL/AML1 ( now referred as ETV6/RUNX1) Rare ( 2%) 16-29% ( most common “t” in children) Favorable Hyperdiploidy >50 7% 25% Favorable Hypodiploidy < 44 2% 5% Unfavorable
- 19. ALL CLINICAL PRESENTATION
- 32. ADULT ALL: LARGE CLINICAL TRIALS Clinical Trials N Age Treatment CR, % DFS, % GMALL 02/84 562 28 BFM 75 39 GMALL 05/93 1163 35 BFM, HD-ARA-C, HD-MTX 87 35-40 CALGB 8811 198 35 BFM, ↑ Cy, ↑ ASP 85 36 CALGB 19802 163 41 BFM, ↑ Cy , ↑ DNR 78 35 GIMEMA 778 28 BFM ± Cy 82 29 MRC-UKALL XA 618 > 15 BFM + early intensification 89 -- MRC/ECOG 1521 BFM + HD-MTX ± SCT 91 38 UCSF 8707 84 27 BFM intensified 93 52 Hyper-CVAD 288 40 Cy, D, AD, HD-MTX, HD-ARA-C 92 38
- 33. ADULT ALL: LARGE CLINICAL TRIALS (CONT’D) Study Study Years References GMALL 02/84 84-90 Hoelzer D, et al. Blood. 1998;71:123-131. GMALL 05/93 93-99 Gökbuget N, et al. Blood. 2001;98:802a. CALGB 8811 88-91 Larson R, et al. Blood. 1995;85:2025-2037. CALGB 19802 99-01 Larson RA. Ann Hematol. 2004;83(suppl 1): S127-S128. GIMEMA 88-94 Annino L, et al. Blood. 2002;99:863-871. MRC-UKALL XA Durrant I, et al. Br J Haematol. 1997;99:84-92. MRC/ECOG 93-04 Rowe J, et al. Blood. 2005;106:3760-3767. UCSF 8707 87-98 Linker C, et al. J Clin Oncol. 2002;20:2464-2471. Hyper-CVAD 92-00 Kantarjian H, et al. Cancer. 2004;101:2788-2801.
- 41. ALL: SCT AT FIRST CR Several trials comparing chemotherapy vs. autologous stem cell transplant vs. Allo-SCT reveal improved survival with allo-SCT in High Risk patients as shown above. Study Endpoint CHT Auto SCT Allo SCT Improved Outcome CIBMTR vs German studies LFS 32% -- 34% NS JALSG 93 OS 40% -- 46% NS LALA 87 OS 35% 48% NS LALA 87 SR OS 45% 51% NS LALA 87 HR OS 20% 44% Allo LALA 94 HR OS 35% 44% 51% Allo GOELAL02 HR OS -- 40% 75% Allo
- 42. ALLO BMT VS AUTO BMT IN PATIENTS WITH PH- ALL: MRC UKALL XII/ECOG E2993 Rowe JM, et al. ASH 2006. Abstract 2. Patients with Ph- ALL aged < 55 yrs in complete remission after induction therapy (N = 919) Sibling Allo BMT (n = 389) High-Dose Methotrexate (3 doses) HLA-matched sibling donor available? Yes High-Dose Methotrexate (3 doses) Auto BMT Consolidation/Maintenance Chemotherapy: 2.5 years (n = 530) No
- 48. L-ASPARAGINASE: MECHANISM OF ACTION* *Sensitivity of ALL cells to asparaginase due to low asparagine synthetase in leukemic cells. Blood L-asparagine L-asparaginase NH3 + L-aspartate Cell L-asparagine Asparagine synthetase Glutamine L-aspartate L-asparagine + Glutamate +
- 61. NELARABINE IN RELAPSED/REFRACTORY ADULT T-ALL/T-LBL 1. Goekbuget N, et al. Blood. 2005;106:47a. Abstract 150. 2. DeAngelo D, et al. Blood. 2002;100:198a. Abstract 743. Study CR PR OS Toxicity GMALL (N = 53) [1] 47% 13% 16% Myelosuppression Neurotoxicity (n = 2) CALGB (N = 38) [2] 26% 5% 32% at Yr 1 Myelosuppression Elevated LFT Neurotoxicity (n = 1)
- 63. ALL – SALVAGE THERAPY
- 64. RELAPSED/ REFRACTORY ALL PROGNOSTIC FACTORS Independent prognostic factors associated with achieving CR during salvage therapy include duration of first CR and platelet count. Several factors are associated with poor survival rates : - short duration of first CR, thrombocytopenia, elevated percent bone marrow blasts, and low albumin level Poor Prognostic Factors for CR Poor Prognostic Factors for Survival Albumin level < 3 g/L* Albumin level < 3 g/L* Duration of first CR < 36 mos* Duration of first CR < 36 mos* Hemoglobin level < 10 g/dL Hemoglobin level < 10 g/dL Platelet count ≤ 50 x 10 9 /L* Platelet count ≤ 50 x 10 9 /L* Percent bone marrow blasts > 50% Percent bone marrow blasts > 50%* Peripheral blood blasts ≥ 1% Percent peripheral blood blasts ≥ 1% White blood cell count > 20 x 10 9 /L
Editor's Notes
- In the last two years, we saw about 4 ALL cases in our institutes – all were in Hispanics.
- Sharp decline in adolescence and then in to adulthood. Among adults, incidence increases after the age of 60
- Bloom syndrome (congenital telangiectatic erythema) is a rare autosomal recessive disorder characterized by telangiectases and photosensitivity, growth deficiency of prenatal onset, variable degrees of immunodeficiency, and increased susceptibility to neoplasms of many sites and types. Fanconi anemia : Excess chromosomal fragility. Includes multiple birth defects, including short stature, microcephaly, microphthalmia, epicanthal folds, dangling thumbs, site of ureteral reimplantation, congenital dislocated hips, and rocker bottom feet
- High remission rates are possible both in children and adults but relapses are common in adults – hence, 5 year survival rates only 35% . The less favorable prognosis for adults with ALL is related to several factors, including a much higher frequency of poor-risk prognostic factors based on disease biology, comorbidities associated with older age that impair the ability to tolerate intensive multiagent chemotherapeutic regimens that have been used successfully in children, subtle differences in the treatment regimens used by medical oncologists treating adults, and treatment compliance.
- SMALL ARROWS IN L3 ARE VACUOLES, VERY LARGE NUCLEOLI ARE SEEN IN L3. L3 – Guarded prognosis, . The L3 cell usually has mature B-cell characteristics - treated using same therapy as for highly aggressive B-cell lymphoma variants ( burkitt-like)
- Divides ALL into 2 major categories: precursor lymphoid neoplasms and mature lymphoid neoplasms. The precursor lymphoid diseases include both B lymphoblastic leukemia/lymphoma and T lymphoblastic leukemia/lymphoma. The new classifi cation further subdivides the precursor B-cell ALL cases by recurring molecular-cytogenetic abnormalities to provide prognostic and therapeutic information and to facilitate the implementation of specific molecularly targeted therapies. Burkitt lymphoma/leukemia is the one subset of ALL that is classified as a mature B lymphoid neoplasm. 3
- Burkitt ALL also called mature B-CELL ALL characterized by distinctive - has a unique immunophenotype with expression of surface immunoglobulin and strong expression of CD20 with distinctive morphologic and cytogenetic features. These ALLs are associated with chromosome translocations involving C-myc PROTOONCOGENE ON CHR 8 ( 8,14) . Myeloid Markers (11,13, 15,33, 65) : Apart from above, Myeloid-associated antigens may be expressed on otherwise typical lymphoblasts . 20 TO 30% ALL cases) The pattern of myeloid-associated antigen expression correlates with certain genetic features of blast cells. CD15, CD33, and CD65 are expressed in ALL with a rearranged MLL gene ( t4.11), and CD13 and CD33 expressed in patients with the ETV6-RUNX1 (also known as TEL-AML1) fusion. A subset of patients coexpress both lymphoid and myeloid markers but do not cluster with precursor T-cell, precursor B-cell, or acute myeloid leukemia in gene expression profiling (biphenotypic). These patients may not respond to myeloid-directed therapy but may attain remission with ALL-directed induction treatment. The presence of myeloid-associated antigens lacks prognostic significance but can be useful in immunologic monitoring of patients for minimal residual leukemia. Pro-B CD19(+),Tdt(+),CD10(-),CyIg(-), Common CD19(+),Tdt(+),CD10(+),CyIg(-), Pre-B CD19(+),Tdt(+),CD10(+),CyIg(+),SmIg(-)
- ALL arises from a lymphoid progenitor cell that has sustained multiple specific genetic damages that lead to malignant transformation and proliferation. Thus, Genetic classification of ALL yields more biological information rather than any other means – genetic classification yields progonostic information and information regarding specific therapies tailored to certain subtypes. Hyperdiploidy > 50 chromosomes for example, seen in 25% of pediatric ALL , associated with favorable prognosis in childhood ALL– and predicts increased sensitivity to anti-metabolites like MTX ( less toxic therapies). In contrast, extreme hyperdiploidy (59 to 84 chromosomes) or hypodiploidy (fewer than 45 chromosomes) is associated with poor outcome and require aggressive and toxic therapies.
- BCR-ABL – 25% ; MLL – 10% and MYC – BURKITT Are the most common of all cytogenetic abnormalities in adults Others – 23%, hypodiploidy 2%, hyper 7%, tel-aml 2%
- TCR, T-cell receptor
- Certain translocations may be associated with poor prognosis and requires aggressive treatment options. Such as above. The gene involved is shown too. More aggressive treatment regimens are recommended for children with t(1;19) and they respond well to such strategies, whereas the addition of tyrosine kinase inhibitor therapy should be considered in patients with t(9;22). Patients with the t(4;11) MLL rearrangement have a significantly poorer treatment outcome than do those without this abnormality and are treated with more intensive chemotherapy and hematopoietic cell transplantation are usually apt for these patients.. Some structural abnormalities are associated with favorable prognosis. They include the t(12;21) ETV6/RUNX1 (formerly referred to as TEL/AML1) rearrangement in B-precursor ALL, which occurs in 20 to 25 percent of cases of childhood ALL [49,50]. CYTOGENETICS must be considered in context with other risk factors in deciding the best therapeutic option. As an example, in one prospective study of 44 children with high-risk ALL, as determined by age, WBC count, and immunophenotype , cytogenetic abnormalities did not independently predict outcome
- ANEMIA, THROMBOCYTOPENIA, NEUTROPENIA – BM Failure. Leukemic infiltration related are : organomegaly, LAD, MEDIASTINAL MASSES, CNS INFILTRATION. Clinically, a case is defined as lymphoma (LBL) if there is a mass lesion in the mediastinum or elsewhere and <25 percent blasts in the bone marrow. It is classified as leukemia (ALL) if there are >25 percent bone marrow blasts, with or without a mass lesion. WHO Minimal criteria for acute leukemia is BM blasts > 20%
- Lymphoblast is more malleable – hence, symptoms of hyperleucocytosis are rare.
- MPO – myeloperoxidase, TdT – terminal deoxynucleotidyl transferase
- IT-MTX, intrathecal methotrexate Principles : Induction of remission, consolidation therapy ( may include chemotherapy vs. Allo HSCT) followed by maintainance rx if consolidatiojn included Chemotherapy. No maintainanence required if consolidation included allo-HSCT except in Ph+ ALL where imatinib is sometimes used in maintainance after allo-HSCT.
- Those with CR has better outcome
- Remission induction includes the following components : Chemotherapy, CNS prophylaxis, Supportive Care and Treatment of complications.
- Induction regimens : Berlin-Frankfurt-Munster (BFM), calgb 8811 – cancer and leukemia group
- BFM, Berlin-Munster-Frankfurt
- MTX, methotrexate; WBC, white blood cell count
- Cranial irradiation and IT chemotherapy combined can cause acute toxicities that may delay post-remission consolidation therapy
- CR, complete remission t(4,11) – MLL - UNFAVORABLE; t(12.21) – TEL/AML – FAVORABLE; TIme to attain CR after induction therapy Pre-B linieage is favorable in pediatric ALL
- Allo SCT, allogeneic stem cell transplant; Auto SCT, autologous stem cell transplant; CIBMTR, Center for International Blood and Marrow Transplant Research; LFS, leukemia free survival; CR, complete remission; MUD, matched unrelated donor , Second CR means a CR after relapse
- Allo SCT, allogeneic stem cell transplant; Auto SCT, autologous stem cell transplant; CHT, chemotherapy; HR, high risk; CIBMTR, Center for International Blood and Marrow Transplant Research; LFS, leukemia free survival; OS, overall survival; ST, standard risk; In LALA 87 Trial, improved outcome noted with allo-SCT in HR patients were as difference in OS was non-significant in SR patients. However, MRC-UK/ALL trial showed the benefit was more for SR patients rather than HR patients which is contradictory to other studies --- however, this study was done from 1993 ----- he results of the Medical Research Council (MRC) UKALL XII/ECOG E2993 trial which was initiated in 1993 to prospectively define the role of HSTC in ALL, were reported in December 2006 . Of note, in newly diagnosed adults with Ph-negative ALL up to 60 years of age, the greatest benefit from allogeneic HSTC was observed in patients with standard-risk ALL (< 35 years of age; WBC < 30,000 for B-lineage ALL or < 100,000 for T-lineage ALL) compared with patients who received chemotherapy alone. For patients with high-risk ALL, allogeneic HSCT had a more potent antileukemia effect, manifested by lower relapse rates than chemotherapy. However, this benefit was abrogated by higher transplant related mortality, resulting in no net survival benefit . These results differ from those reported in the aforementioned studies. The benefit of allogeneic HSCT might have outweighed the risks in high-risk patients if the nonrelapse mortality rate had been lower than the reported rate of 39%. Considering that this study began enrolling patients more than 15 years ago, it is possible that HSCT-related mortality would be lower at the present time , resulting in an improvement in overall survival, even among high-risk patients. It is also possible that some patients younger than 35 years of age would have been classified as having high-risk disease because of unfavorable cytogenetics and, therefore, would have experienced less transplant-related mortality. This study also confirmed that autologous HSTC cannot replace consolidation or maintenance treatment in any risk group.
- ALL, acute lymphoblastic leukemia; Allo, allogeneic; Auto, autologous; BMT, bone marrow transplantation; HLA, human leukocyte antigen; MRC, Medical Research Council; Ph-, Philadelphia chromosome negative; ECOG, Eastern Cooperative Oncology Group
- OS, overall survival; WBC, white blood cell count
- EFS, event-free survival; OS, overall survival
- Mature B-cell ALL has high cure rates after consolidation and does not require maintainance.
- The drug acts by depleting serum asparagines, which can be reproduced in normal cells by asparagine synthetase. However, ALL cells are unable to produce their own asparagine and, therefore, are dependent on the plasma for this amino acid. Plasma asparagine depletion leads to inhibition of protein synthesis, which depletes RNA and DNA synthesis, resulting in apoptotic cell death of the leukemic cells
- CNS, central nervous system Always test dose must be administered before L-ASPARAGINASE
- CR, complete remission; Ph+, Philadelphia chromosome positive The prognosis for patients over the age of 60 remains poor, with a DFS rate of < 10%. Older adults with ALL are excellent candidates for novel therapeutic approaches.
- CR, complete remission; G-CSF, granulocyte-colony stimulating factor
- In ALL, Ph+ is seen only with immunophenotype pre-B ALL. PH+ IS AUTOMATICALLY A HIGH RISK ALL SCT, stem cell transplant
- CR, complete remission; SCT stem cell transplant Imatinib achieves more durable response and gives time until a donor can be found ---hence, increases access to HSCT fore more patients.
- Role of second generation TKIs in PH+ ALL is still under investigation . However, it may have somr role in relapsed PH+ALL after imatinib. CCyR; complete cytogenetic response; CHR, complete hemoatologic response; MCyR, major cytogenetic response; NEL, no evidence of leukemia (CHR but absoulte neutrophil count < 1,000 and platelets 100,000
- CNS, central nervous system; CR, complete remission; FAB, French-American-British; LDH, lactic dehydrogenase ; MTX, methotrexate Incorporating Rituximab has resulted in an increased survival rates > 70%.
- CR, complete remission; PCR, polymerase chain reaction
- CALGB, Cancer and Leukemia Group B; GMALL, German Multicenter Study Group for Adult Acute Lymphocytic Leukemia; LFT, liver function test In a recent study by the Cancer and Leukemia Group B, nelarabine treatment produced complete remission rates of 26% with minimal toxicities in relapsed/refractory ALL patients.
- Outcomes of salvage therapy in adult acute lymphoblastic leukemia (ALL) patients remains poor. Complete remission (CR) rates are typically < 50% and long-term disease-free survival is rare. I
- Salvage chemotherapy regimens are structured according to outcomes from frontline therapy. Some newer agents have been approved in the relapsed setting. After second CR, allo –SCT in all patients!!!!!!!!!!!
- IT, intrathecal
- Allo SCT, allogeneic stem cell transplant; auto SC, autologous stem cell transplant
- CR, complete remission; MRD, minimum residual disease