Leukemia

SUMMARY

  • Indications for RT
  • Acute Lymphoblastic Leukemia
  • Cranial RT for CNS-prophylaxis in high-risk patients, CNS involvement at diagnosis or relapse
  • Testicular RT for relapse in the testis
  • TBI as part of the myeloablative regimen in BM transplant in ALL, AML, and NHL

Epidemiology

  • Most common childhood tumor, 30%.
  • 2500 new cases a year.
  • Most common type is ALL (acute lymphoblastic leukemia 80%) and then AML (acute myeloblastic) (20-25%). Rare to have a chronic leukemia in childhood.
  • Associated syndromes include Fanconi, Bloom, Down\’s, and Wiskott-Aldrich syndromes.
  • Main role for radiation is CNS prophylaxis where the CNS is a sanctuary site. Other forms of CNS prophylaxis include triple IT medication.
  • Patients at high risk for CNS failure include: high WBC count, young <2 years, FAB lymphocyte, and leukemia syndrome (Tcell, HSM, and lymphadenopathy).

ALL General

  • Presents between 2-10 years with median age of 4 years.
  • It is the clonal expansion of dysregulated immature lymphoid cells where B cell dominates at 80% (where 55% are derived from the pre-B lymphocyte lines). They express the CD10 on the cell surface (CALLA +). The remaining is **T cell **in origin that is 15-20% of the cases.
  • B cells = younger, wide range of clinical manifestation, nl WBC, CD 19
  • T cells = Older (>10), assoc with extramedullary invol, ++WBC, CD 7
  • Genetics: 75% have some chromosomal translocation. B cell related to t(9;14) and \~5% t(9;22) the Philadelphia chromosome ( unfavorable). T-cell is related to t(11;14)

Lymphoblastic Lymphoma

  • The difference between ALL and lymphoblastic lymphoma is arbitrary
  • If > 25% bone marrow is involved then it is considered to be ALL and not stage IV Lymphoblastic lymphoma
  • Lymphoblastic Lymphoma typically present with large mediastinal or neck nodes.

Risk Categories/Staging

Standard Risk

  • WBC < 50K and age < 10 y

High risk for CNS (XRT indications)

  • WBC > 50K or age > 10 y or <1 yr
  • T cell1
  • BCR/ABL
  • Ph+ ALL: t(9:22), translocation
  • presence of (4;11) translocation
  • CNS-3 involvement (found in < 5% of initial presentation of patient with ALL)
  • Slow responders (ie. Patients who do not go to complete remission in certain amount of time like 2 weeks)

Definitions

  • CNS-1 : CSF analysis negative
  • CNS-2 : CSF < 5/uL WBC and blast(+) OR >= 5/uL WBC
  • CNS-3: CSF >= 5/uL WBC and blast(+) or cranial nerve palsy
  • M1: <1% blast in BM (bone marrow)
  • M2: 5-25% blast in BM
  • M3: > 25% blast in BM

ALL Presentation

  • The replacement of the BM cells with leukemic cells results in neutropenia (infections), thrombocytopenia (bruising and bleeding), and anemia (malaise).
  • Can also have adenopathy, bone pain, and hepatosplenomegaly.
  • WBC is <10 (50%), 10-50 (30), 50-100 (10%) and >100 (10%).
  • Ophthalmic presentation can be seen in 30% of the patients. Can have optic disc infiltration.
  • Boys (T cell)> Girls, Whites> Blacks

ALL Chemotherapy

  • There are 4 regimens: initial remission induction, intensification (consolidation therapy) to eliminate blast cells, prevention of CNS disease, and continuation therapy with therapy lasting 2-3 years.
  • For the high-risk group the second part is the most important part.
  • Induction therapy: prednisone, vincristine, L-asparaginase., +/- daunorubicin
  • Intensification: high dose methotrexate, VM-16, and L-asparaginase., 6-MP
  • Maintenance therapy: 6MP and systemic weekly methotrexate (for all except mature B-cells), chronic chemo 30-36 mos
  • Berlin/Frankfurt/Munser (BFM) includes treatment with prednisone, vincristine, L-asparaginase, cyclophosphamide, cytosine arabinoside and intrathecal MTX. Complete remission rate is 75%.
  • Long term ALL free survival 80 to 90%; Std risk DFS 80%; High risk 70 to 80%

CNS Prophylaxis

Standard Risk Patients: IT MTX
High-risk patients need CNS- prophylaxis with
1. Cranial-spinal RT
2. Cranial RT + IT chemotherapy

Radiation Dose:

  • Standard prophylaxis CrI dose: 12 to 18Gy in 150 to 180 cGy.2
  • CNS + meningeal leukemia: 18 to 24Gy + IT chemotherapy.
  • CN palsies: 10-15 Gy to Base-of-skull at 150 cGy/fx.

Radiation Technique

  • Cranial Field: Leukemia cells can often extend into the subaracnoid space thus the entire subarachnoid space need treatment. The bottom is at C2 and includes the posterior retina and orbital apex to encompass the extension along the optic nerves. Make sure to include the cribiform plate, temporal fossa, base of skull, and posterior fossa. Use lateral fields with half beam block and the central axis between the limbus and the lateral canthus -OR - 4 to 5 degree gantry angle to spare lens.
  • Spinal field: the caudal margin of the spinal field must extend below the lower limit of the thecal sac which is determined by sagittal MR.
  • **SJCRH ** **study VI **(upfront CSI 24 Gy or at relapse)
  • CNS relapse rate without CSI is 67% regardless of WBC count at presentation
  • Of the 67% relapse only 25—35% were salvaged
  • CNS relapse rate with CSI is 4%
  • Both survival benefit and functional benefit seen
  • CCG 101: short term IT MTX (6 x Rand) had CNS failure rate of 35% even for low risk patients
  • Other trials showed equivalence of 18Gy and 24 Gy
  • German BFM—risk adapted approach—balance CrI and HdMTX
  • Std riskno CrI
  • CrI most beneficial WBC > 100,000, T-cell
  • Decresed dose to 12 Gy/8 fx

. CSI associated with growth, endocrine, and cognitive problems as well as risk of secondary tumors (4% RT alone vs 12% RT + MTX

  • CrI (craniCal RT) + IT MTX **is equivalent to **CSI with LF rate of 5%. These results are seen with the BFM and DFCI regimens.
  • Triple (ex: IT with MTX, cytosine arabinoside, and prednisone) was compared to IT MTX + CrI and the CNS relapse were 4% in both groups.** POG:
  • Long-Term IT (9 or more cycles)
  • In general no radiation arms seems to have few percent higher CNS relapse rates but EFS is same as they tend to have better extra-cranial control.**
  • CALGB: compared intermediate dose IV+IT MTX versus 24Gy + IT-MTX with RFS was 73% versus 57% but CNS RFS was 72% versus 92%

CNS Relapse
** 10% (75% asx)
Tx: Reinduction, IT chemo, RT or CSI alone
EFS better if relapse > 18 mos after initial remission (83% vs 46%)
POG: adv of chemo before CSI
Current Recommendation is CSI (18Gy)
Extramedullary sites**

  1. Testicular: 10 to 20% of all failures in boys; Late (36mos)

Tx: Systemic chemo + consolidative RT to both tyesticle with en face e; 20 to 24 Gy

  1. Anterior chamber of eye 12 Gy/6 fx

**AML **

  • 20% of all cases with usually older patients; Increased association with Downs
  • Organomegaly Less common; Deposits (Chloromas) seen
  • 15% CNS at dx; Initial WBC < 50,000, Auer rods, t(8:21)
  • Treat with induction daunorabine, + cytarabine , thioguanine

30 to 40% DFS; Then BML (POG/CCG)

  • Long-term survival is 10%.
  • RT (radiosensitive)
  • Chloroma or local manisfestation
  • 12Gy sufficient

BMT

  • Allows higher doses of cytolethal agents
  • Leukemia, malignant lymphomas, intrinsic hemo d/o
  • Alogenic or autologous
  • Involves "conditioning" regiment
  • High dose CY and TBI

TBI

  • Purpose: Eliminate residual lymphoblast/myeloblast
  • Immune suppress host so donor marrow accepted
  • variety of regimen available
    • 12Gy/6fx/3 days (2 Gy bid)
  • Vol: Entire body cavity, varity of physical configurations, AP/PA
  • Technical considerations: Dose to lung, kidneys
    • 1/2 value lung blocks
    • Lens shield not conventionally used with leukemics due to orbital concerns, but in practice this may not be an issue.
    • MSKCC use 4-Gy electron testes boost in 1 fraction for boys with leukemia
    • No advantage to splenic RT in randomized study
    • Some boost residual high risk areas like gross disease

Testicular Leukemia

  • Occult disease is found in 25% of boys
  • Clinically overt disease manifest as painless testicular enlargement that is often unilateral, but is infrequent.
  • Surgery: **Testicular biopsies during maintenance or at conclusion is no longer done as it is inaccurate.
  • Testicluar relapse** occurs in < 5% of cases in the current era of intensive therapy.
  • No prophylactic scrotal RT as RT would cause permanent sterility.
  • Relapse
  • Both systemic and local therapies are used
  • Re-induction RT consists of 24-26 Gy in 2Gy fractions to entire scrotal contents.
  • CNS-directed treatment is also needed.
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