Radiation Oncology/Leukemia/ALL

Acute Lymphoblastic Leukemia Risk of Relapse Clinical Age WBC count Biological Histology/immunophenotype Cytogenetics Gene identification Response based Morphology (BM Bx/aspirate) Minimal Residual Disease Lymphomatous presentation (1855175) Risk groups: Low - age 2-9 inclusive, WBC < 10,000; no L2 morphology and boys with plts < 100,000 Intermediate - all others; includes pts who are low risk but have L2 morphology or boys with plts < 100,000 High - WBC > 50,000; pts who are intermediate risk but have L2 morphology Adults with ALL: High risk: age > 35, WBC > 30,000, null cell phenotype, Ph+, remission after more than 4 weeks of intensive chemo Have a 18-28% chance of continuous CR at 5 yrs Regular risk 60% 5-yr DFS CNS disease See also: Radiation Oncology/CNS/CSF involvement CNS 1 - Negative cytology (no blasts) CNS 2 - +cytology, < 5 WBC/microliter CNS 3 - +cytology, >=5 WBC/microliter, or any CN lesion Gilchrist 1994 CNS involvement at diagnosis in 3% of children with ALL. CNS involvement is more common in ALL, rare in AML (except for the variant acute myelomonocytic leukemia, AMML), and rare in CML and CLL. Risk in AMML is 20%. 5-10% risk in adults with ALL. Roles for Radiation CNS prophylaxis CNS Therapy (active disease) TBI Testis prophylaxis(sanctuary sites) Palliation BMT Indications for allogeneic hematopoietic stem cell transplantation (HSCT): Relapse, unfavorable cytogenetics, induction failure. High risk patients (relapsed or t(9;22) (Philadelphia) may benefit from BMT Conditioning regimens prior to HSCT: purpose is to prevent graft rejection and eliminate leukemic cells. Regimen may consist of chemotherapy alone or chemotherapy + TBI. There is a suggestion of improved outcomes with TBI. Please see the TBI page for technical details TBI - Socio et al, Blood 2001 CNS prophylaxis Indications: Overt CNS involvement at time of diagnosis High risk disease <1 yo, >10 yo WBC > 50,000 T-cell ALL Philadelphia chromosome (bcr-abl translocation) PCI for CNS prophylaxis as frontline treatment for patients with ALL led to an increase in survival in the 1960s. However, toxicity from PCI is significant, particularly with early trials using 24 Gy Dose can be reduced to 12-18 Gy or eliminated entirely if appropriate systemic and intrathecal chemotherapy is used, with lower toxicity DFCI Consortium protocol: cranial RT 12 Gy indications (per 17971588): T-cell phenotype, CNS-3 status at diagnosis, or residual disease after induction COG AALL0232 protocol (High risk B-precursor ALL) Prophylactic 12 Gy cranial RT Slow early responders (day 15 BMBx shows M2/M3 disease, or day 29 BMBx shows MRD) MLL rearrangement Patients pre-treated with steroids (e.g. for bronchiolitis symptoms) Therapeutic 18 Gy cranial RT CNS 3 disease Therapeutic 24 Gy testicular RT Initial testicular involvement, and continued evidence of testicular involvement at the end of Induction Dose overview: Standard risk, CNS 1-2: chemotherapy Standard risk, CNS 3: WBRT 18 Gy High risk, CNS 1-2: WBRT 12 Gy High risk, CNS 3: WBRT 18 Gy Overt disease (CN palsy or by MRI): WBRT 24 Gy first, then chemo Treatment of CNS disease See also: Radiation Oncology/CNS/CSF involvement Therapeutic Cranial Irradiation -5% of those on initial presentation -CNS failure See appropriate protocol for chemotherapy regimen, individual risk-adapted, and response criteria to stratify by risk category. Dose Varies on protocol 24 Gy in past, no longer used. 18 Gy (standard dose) associated with decreased risk of CNS complications 11443604 - Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92 (1): 15-22, 2001. 12 Gy has been used more recently in European trials 10828010 - Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000. Fraction size Usually 180 Sometimes 160 (thought to be lower neurocognitive effects) Volume Cranial radiation only (no spinal irradiation) (Sanctuary Therapy: A Randomized Trial of 724 Children with Previously Untreated Acute Lymphoblastic Leukemia A Report from Childrens Cancer Study Group Nesbit et al. CANCER RESEARCH 42. 674-680, February 1982) Areas to watch Cribiform plate (reported site of failure for medulloblastoma) Temporal lobes Treatments: CCG trials from 1971-78 used cranial RT + intrathecal MTX but no spinal RT. CSI was found to be more effective than cranial RT in treating pts with CNS relapse. (Willougby, MRC, 816410, 1976) CCG trials from 1978-83 used 24 Gy cranial + 12 Gy spinal given during consolidation phase along with systemic and intrathecal chemo. CNS disease at diagnosis was not an independent prognostic factor, thereby indicating the effectiveness of CNS treatment regimens used. CCG trials from 1983-89 used more intensive chemotherapy. Reduced spinal dose to 6 Gy in those treated with intensive consolidation phase in order to limit hematopoietic toxicity. Children's Cancer Group, CCG, 1996 (1983-89) - 8823255 — "Craniospinal irradiation for acute lymphoblastic leukemia with central nervous system disease at diagnosis: a report from the Children's Cancer Group." Chewlow JM et al. Int J Radiat Oncol Biol Phys. 1996 Aug 1;36(1):19-27. Prospective. 53 pts with CNS disease on 4 trials for children > 1 yr -- CCG-104(low-risk), CCG-105 (int-risk), CCG-106 (high-risk), CCG-123 (lymphomatous presentation). Pts with CNS disease received CSI and intrathecal chemo. Pts with CNS disease treated with intensive consolidation chemo received 24 Gy cranial RT + 6 Gy spinal (each at 2 Gy/fx). Pts not treated with intensive consolidation received 24 Gy / 12 Gy. All received intrathecal MTX and/or Ara-C. Median f/u 74 mo. 5-yr EFS for all CNS+ pts was 69%, compared to 67% for those who were CNS-. 5-yr freedom from isolated CNS relapse was 90% vs 94%. No difference between 6 Gy and 12 Gy group. Conclusion: CNS disease at diagnosis is not a poor prognostic factor for children treated with intensive chemo + craniospinal RT + intrathecal chemo. 6 Gy of spinal RT + 24 Gy cranial RT is appropriate. Meta-analysis, 2003 12721257 -- "CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials." (Clarke M, J Clin Oncol. 2003 May 1;21(9):1798-809.) Individual data on 2848 patients randomly assigned to CNS-directed therapy prior 1993 10-year EFS: RT + IT-chemo 64% vs. high-dose IT-chemo 63% (NS) Conclusion: "Radiotherapy can be replaced by long-term intrathecal therapy. Intravenous methotrexate gives some additional benefit by reducing non-CNS relapses." Prophylactic CNS RT CCG trials High Risk CCG-106 1993 8229139 — "Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106." Gaynon PS et al. J Clin Oncol. 1993 Nov;11(11):2234-42. Lymphomatous Presentation CCG-123 1993 8262820 — "The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group." Cherlow JM et al. Int J Radiat Oncol Biol Phys. 1993 Dec 1;27(5):1001-9. Intermediate Risk CNS RT not standard part of protocols Isolated CNS relapse rate is <5%, though it accounts for 25-30% of all failures Testicular relapse rate is <1% CCG-1991 Comparison of single delayed intensification and double delayed intensification within dexamethasone-based regimen CCG-1952 2006 16609069 -- "Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group." (Matloub Y, Blood. 2006 Aug 15;108(4):1165-73.) Randomized. 1018 patients to intrathecal MTX or intrathecal MTX+cytarabine+hydrocortisone after induction. 6-year EFS: IT-MTX 83% vs. IT-Triple 81% (NS). More testicle and BM failures with IT-Triple CNS failure: IT-MTX 5.9% vs. IT-Triple 3.4%. Conclusion: IT-Triple improves CNS failure, but no OS difference due to more testicle/BM failures CCG-1922 (children 1-10 y/o, WBC <50K) 2003 12531809 -- "Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group." (Bostrom BC, Blood. 2003 May 15;101(10):3809-17.) Randomized. 1060 patients randomized to dexamethasone vs. prednisone (standard arm). Second randomization oral vs. IV 6-mercaptopurine. CNS therapy IT-MTX 6-year EFS: dexamethaseon 85% vs. prednisone 77% (SS). No difference for 6-MP. OS 93% vs. 91% (NS) Isolated CNS failure: dexamethasone 3.7% (25% of all failures) vs. prednisone 7.1% (31%) (SS) Testicular failure: dexamethasone 0.2% vs. prednisone 0.5% Conclusion: dexamethasone-based regimen superior over prednisone CCG-1891 (children 1-10 y/o, WBC <50K) 2002 11806983 -- "Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. (Lange BJ, Blood. 2002 Feb 1;99(3):825-33.) Successor study to CCG-105. Young (<10) patients with intermediate-risk ALL. Randomized 1204 patients to single delayed intensification phase (DI), double DI, or DI + vincristine/prednisone pulsing. No RT CNS prophylaxis 6-year outcome: EFS 79% (double DI best at 83%), OS 89% (no difference) Isolated CNS failure: DI 7.9% (36% of all failures), double DI 6.7% (35%), DI+VP 4.8%(35%) Testicular failure: DI 2%, double DI 1%, DI+VP 2% Conclusion: double delayed-intensification phase improves EFS CCG-191P Randomized. 181 patients. VHD-MTX vs. CRT + intrathecal methotrexate Equivalent survival. However, patients treated with CRT had poorer performance on neurocognitive testing over time. CCG-105 1993 8445428 — "Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial." Tubergen DG et al. J Clin Oncol. 1993 Mar;11(3):527-37. 1993 8445427 — "Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report." Tubergen DG et al. J Clin Oncol. 1993 Mar;11(3):520-6. CCG-141 7033075 (1981), 6336986 (1983) Low Risk CCG-104 Unclassified CCG-101 (1972-1974) 1982 7034927 -- "Sanctuary therapy: a randomized trial of 724 children with previously untreated acute lymphoblastic leukemia: A Report from Children's Cancer Study Group." (Nesbit ME, Cancer Res. 1982 Feb;42(2):674-80.) Randomized. 724 children. 4 methods of prophylactic sanctuary therapies: 1) 24 Gy CSI + 12 Gy extended field RT to liver, spleen, kidneys, lower abdomen, gonads, 2) 24 Gy CSI, 3) 24 Gy PCI + IT-MTX, and 4) IT-MTX alone 8-year OS: 56%, EFS 52% The 3 arms containing RT comparable at preventing CNS relapse, and superior to IT-MTX alone. If WBC >20K, best arm was PCI + IT-MTX PCI 24 Gy vs. 18 Gy = similar rates or relapse Conclusion: CSI not necessary BFM Trials BFM Review, 2000 (1981-1995) 11187912 -- "Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster." (Schrappe M, Leukemia. 2000 Dec;14(12):2205-22.) Four consecutive trials (ALL-BFM 81, 83, 86, 90). 4440 children. 8-year EFS: BFM-81 66% improved to BFM-90 76%. If good early response (~90% patients), then 8-year EFS 80% Isolated CNS relapse: BMF-81 5.3% improved to BFM-90 1.1% Major findings: 1) Re-intensification is crucial part of treatment, even for low risk patients 2) Cranial RT can be reduced to 12 Gy, or even eliminated if replaced by intensive systemic therapy and IT-MTX 3) Maintenance for 24 months better than 18 months 4) Inadequate response to initial prednisone defines ~10% high risk patients High risk patients: Poor prednisone response, hyperleukocytosis, age <1 year, Philadelphia chromosome St. Jude's Trials SJ Total Therapy XV (2000-2007) 2009 19553647 -- "Treating childhood acute lymphoblastic leukemia without cranial irradiation." (Pui CH, N Engl J Med. 2009 Jun 25;360(26):2730-41.) Prospective. 498 consecutive patients with ALL. No PCI. Low risk (age 1-10, WBC <50K, DNA index >1.16, t(12;21)); high risk (t(9;22)). Final risk status determined by level of MRD (>1% after induction was high risk). Treatment individualized. Outcome: 5-year EFS 86%, OS 93%. 5-year risk of isolated CNS relapse 2.7%, any CNS relapse 3.9% Predictors for CNS relapse: t(1;19), CNS involvement at diagnosis, T-cell immunophenotype Conclusion: Prophylactic cranial irradiation can be safely omitted from treatment of childhood ALL SJCRH XIII (1991-1994) 1998 9657739 -- "Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia." (Pui CH, Blood. 1998 Jul 15;92(2):411-5.) Prospective. 165 patients. Intensified intrathecal chemo (MTX+hydrocortisone+Ara-C) for better CNS control. RT (22%): PCI 18 Gy only for high risk (B-cell >100K, T-cell >50K or Ph+, 18%); PCI 24 Gy only for CNS leukemia (CNS-3, 4%) 5-year isolated CNS failure: low risk 2 failures (1%), high risk 0 failures 5-year EFS: 80% Conclusion: Early intensification of intrathecal chemo reduces risk of CNS relapse, with PCI reserved only for high risk patients SJCRH XII (1988-1991) RT same as XI (High risk or CNS leukemia: PCI 18 Gy, otherwise no RT) SJCRH XI (1984-1988) High risk or CNS leukemia: PCI 18 Gy, otherwise no RT SJCRH X (1979-1983) Standard risk: PCI 18 Gy + IT MTX vs. high-dose MTX; high risk: PCI 24 Gy Lower CNS failure in PCI group Higher testis and BM failure rate in PCI arm Stratified by WBC (>25k), increase risk of CNS failure in HDMTX arm SJCRH IX (1976-1979) RT PCI 24 Gy + some IT-MTX SJCRH VIII (1972-1975) Everyone RT PCI 24 Gy + IT-MTX. Maintenance randomized to 4 different regimens: 1) IV-MTX, 2) oral MTX + 6-MP, 3) #2 + cyclophosphamide, 4) #3 + ara-C CNS relapse least in oral MTX + 6-MP arm Significant leukoencephalopathy (lethargy, SZ, spasticity, paresis, ataxia) in IV-MTX concurrent with PCI arm SJCRH VII 1981 6115282 -- "Leukaemia remission and survival." (Simone JV, Lancet. 1981 Sep 5;2(8245):531.) Randomized to CSI 24 Gy vs. PCI 24 Gy + IT-MTX No difference in outcomes Conclusion: No need for CSI if IT-MTX given for spinal control SJCRH VI 1978 102418 -- "Preventive central nervous system irradiation in children with acute nonlymphocytic leukemia." (Dahl GV, Cancer. 1978 Nov;42(5):2187-92.) Randomized to +/- CSI 24 Gy CSI to 24 Gy in 15/16 fxs reduced isolated CNS relapse from 67% to 4% No change in overall survival due to significant and persistent BM failures Dose reduction to 12 Gy not possible with chemo of that time SJCRH V 1973 4516522 -- "Comparison of two methods of preventing central nervous system leukemia." (Aur RJ, Blood. 1973 Sep;42(3):349-57.) All patients given CNS RT 24 Gy Addition of craniospinal radiation significantly improved outcomes over previous studies (I-IV) SJCRH I-IV (1962-1966) 1972 4509105 -- ""Total therapy" studies of acute lymphocytic leukemia in children. Current results and prospects for cure." (Simone J, Cancer. 1972 Dec;30(6):1488-94.) No CNS RT given Conclusion: 1) combination chemo is superior to sequential administration of single agents, 2) full-dose is superior to half-dose chemotherapy DFCI Consortium Trials DFCI Consortium 95-01 (1996-2000) Multiple randomizations. 491 patients with ALL; 272 standard risk (B-cell, WBC <50K, Age 1-10, no CNS lymphoblasts, no mediastinal mass, no Philadelphia chromosome), 219 high risk. Standard risk: 1) triple IT chemo vs. double IT chemo + Cranial RT 18 Gy BID, 2) Erwinia vs. Escherichia coli asparaginase. High risk: 1) doxorubicin vs. doxorubicin + dexrazoxane, 2) Hyperfractionated (0.9 Gy BID to 18 Gy) versus daily RT (1.8 Gy daily to 18 Gy) 2007 17003366 -- "Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia." (Moghrabi A, Blood. 2007 Feb 1;109(3):896-904. Epub 2006 Sep 26.). Median F/U 5.7 years Outcome: Standard risk: no difference between triple IT chemo and double IT chemo with cranial RT; Erwinia asparaginase worse EFS. High risk: 1) dexrazoxane no benefit Conclusion: Intensive (triple) intrathecal chemo as effective as cranial RT in standard risk patients Other Trials Odense, 1995 (Denmark) 7895752 -- "Prolonged intrathecal chemotherapy replacing cranial irradiation in high-risk acute lymphatic leukaemia: long-term follow up with cerebral computed tomography scans and endocrinological studies." (Hasle H, Eur J Pediatr. 1995 Jan;154(1):24-9.) Prospective. 21 children with high-risk ALL. Treated with prolonged intrathecal triple therapy (MTX, hydrocortisone, Ara-C) 5-year EFS: 79% CNS relapses: none Side effects: 1 child with cortical atrophy, 5 children with delayed bone age, no hormonal abnormalities Conclusion: Extended IT-chemo may provide effective protection with low risk RT Toxicity DFCI Consortium Trial 95-01 Randomized. See above for full protocol information. Subset 164 patients with standard-risk ALL treated with Arm 1) 18 Gy CRT + double IT chemo vs. Arm 2) triple IT chemo 2007 17971588 -- "Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01." (Waber DP, J Clin Oncol. 2007 Nov 1;25(31):4914-21.). Neuropsychological testing at median 6 years Outcome: cognitive function for both groups in average range (median IQ ~100), prevalence of children in special ed comparable. Significant difference in speed of information processing Conclusion: minimal difference between cranial RT and intrathecal chemo alone. Preferable to avoid CRT, but if necessary, CRT 18 Gy may not add risk for neurotoxicity Toronto, 2006 16921038 -- "Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate." (Spiegler BJ, J Clin Oncol. 2006 Aug 20;24(24):3858-64.) Retrospective review. 79 patients with high-risk ALL treated on protocols. CNS prophylaxis either CRT 18 Gy, or high-dose MTX, or very-high dose MTX. Neurocognitive assessment done in mean 10.5 years after Dx (5-20 years) Outcome: no difference between either MTX dose and population mean; CRT did ~1 STD worse (clinically significant, since many require special academic accommodations) Conclusion: "Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes." St. Jude's, 2003 (1962-1992) 12917300 -- "Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia." (Pui CH, N Engl J Med. 2003 Aug 14;349(7):640-9.) Retrospective. 856 patients with no recurrence treated on 13 consecutive clinical trials (out of 2069 treated). Min F/U 10 years 2nd neoplasms: 41/44 RT-related (cumulative risk at 20 years RT 21% vs. no RT 1%) Death rate: standardized mortality ratio to US population - RT 1.9 (SS) vs. no RT 1.7 (NS) Unemployment: men RT 15% vs. no RT 5%; women RT 35% vs. no RT 5% Conclusion: children with ALL who did not receive RT can expect normal life; RT is associated with risk of second neoplasms, slight excess mortality, and unemployment NCI, 1994 7933424 -- "Educational attainment in long-term survivors of childhood acute lymphoblastic leukemia." (Haupt R, JAMA. 1994 Nov 9;272(18):1427-32.) Retrospective. 593 adult survivors of ALL, 409 sibling controls treated in 23 CCG centers More likely to enter special education, RR 3.4 (SS) or learning disability, RR 3.6 (SS). Risk increased with increasing dose of cranial RT Same probability of finishing high school, or earning bachelor's degree CNS RT 24 Gy or age <6: less likely to enter college (RR 0.67) Conclusion: "This large study demonstrates that childhood acute lymphoblastic leukemia survivors have a greater likelihood of being placed in special education or learning disabled programs than their siblings, but that most are able to overcome these problems. Dose of cranial radiotherapy and age at diagnosis are the most important education-related risk factors." Refs to Add POG 7420 Gilchrist 1994 Krull 2013 (JCO Vol 31, Number 35, December 10, 2013, pp. 4407-4415) Review articles CNS treatment: 12525506 — "Toward optimal central nervous system-directed treatment in childhood acute lymphoblastic leukemia." Pui CH et al. J Clin Oncol. 2003 Jan 15;21(2):179-81. CNS treatment: 16215818, 2005 — "Leukemic and lymphomatous meningitis: incidence, prognosis and treatment." Chamberlain MC et al. J Neurooncol. 2005 Oct;75(1):71-83. ALL treamtent: 16407512 — "Treatment of Acute Lymphoblastic Leukemia." Pui CH et al. NEJM. 2006 Jan 12;354(2):166-178. Keywords: ALL, radiotherapy, radiation