POST REMISSION THERAPY IN ALL DR. R. RAJKUMAR III YR POST GRADUATEDEPARTMENT OF MEDICAL ONCOLOGY
DISCOVERY OF LEUKEMIA Craigie and Bennett described a case of suppuration of the blood in 1845. Subsequently referred to the disease as leukocythemia Rudolph Virchow, also in 1845, described a similar case, but did not think this simply pus in the blood and related it to simultaneous splenic enlargement. Subsequently referred to the disease as Weisses Blut then suggested the term leukemia
TREATMENT – EARLY OBSERVATIONS 1865: Lissauer reported response to “Fowler’s solution” (arsenious oxide) 1903: Response of leukemia to splenic radiation in chronic leukemia Accidents in first and second world wars led to recognition of effect of mustard gas on lymph nodes and bone marrow 1942: Gilman and Phillips gave mustard to mice, then patients with lymphoma with some response
TREATMENT – MODERN ERA Sidney Farber attempted to treat leukemic blasts (cf. megaloblasts) with folic acid (identified in 1941, synthesized in 1946) and noted worsening Subsequently gave an antagonist (4- amino pteroylglutamic acid, aminopterin, synthesized by Seeger) to children and observed remissions 4 lasting for several months (reported 0 0 2 1948)
TREATMENT – OTHER DRUGS 1949: ACTH, cortisone and prednisone 1940s and 1950s: Elion and Hitchings study purine metabolism and develop antimetabolites 6-MP and 6-TG 1953: Burchenal gave 6-MP to children with leukemia and introduced triple therapy consisting of 6-MP, antifolate and steroid (one long term survivor) 1959: Cyclophosphamide synthesized by Brock and shown active in ALL by Fernbach et al 1962: Vincristine shown to be active
DISCOVERY OF PRINCIPLES 1950s and 1960s, – Lloyd law develops mouse leukemia (L1210) – Skipper, Schnabel et al, apply mathematical models and demonstrate that cancer cells persist even when the mice are in CR – Also showed dose response relationship – Led to the notion that treatment must be continued after leukemia no longer detectable – Showed (Law) that cells resistant to 6-MP may respond to MTX – multiple drugs may be better 4 0 0 2
Combination Chemotherapy 1962: Freireich and Frei showed that the four available anti-leukemic drugs VAMP gave better results: – VCR, – MTX (amethopterin) – 6-MP – prednisone A few patients achieved long term survival 04 20
TREATMENT – ST JUDE 1962: St Jude Hospital founded. First Director, Donald Pinkel Grappled with problem that although complete remissions could be achieved, only a small percentage of patients (<5%) achieved long term survival Identified obstacles to cure: drug resistance, meningeal relapse, 4 0 toxicity, pessimism 0 2
TOTAL THERAPY St Jude initiated the concept of treatment phases: – Remission induction (usually three drugs) – Intensification or consolidation (different drugs) – Prevention of meningeal leukemia (CNS irradiation) – Continuation therapy (6-MP and MTX) Treatment cessation after 2-3 years 04 Objective - CURE 20
CNS Prophylaxis Total therapy gave better but still poor results (7 of 41 children long term survivors): – Pneumocystis pneumoniae developed in many (probably from cranio-spinal irradiation) – Relapse in meninges still a major problem Used increased dose of cranial radiation; in 1967, 24cG, with IT MTX 4 – Dramatic improvement - 50% long term 0 0 survival 2
GERMAN CONTRIBUTIONS 1965: Formation of Deutsche Arbeitsgemeinschaft für Leukämie Forschung und Behandlung in Kindersalter (38 hematological oncologists). Reihm used aggressive therapy with similar survival rate to St Jude (50%) 1970: Formation of Berlin-Frankfurt-Munster group – based on aggressive 8-drug therapy – Late re-induction improves prognosis in all patients – Poor response to prednisone in first week indicates very poor prognosis – Progressive improvement on structure of treatment protocols
ALL: TYPICAL TREATMENT Induction, consolidation, maintenance phases – CNS prophylaxis with IT-MTX CNS Prophylaxis (IT-MTX) Induction Consolidation Maintenance Over a period of 2-3 years months
Treatment of ALL: BFM- Based Model Induction phase I (4 weeks) – Prednisone, vincristine, daunorubicin, L- asparaginase – No benefit to adding cyclophosphamide, high- dose cytarabine, or high-dose anthracycline Induction phase II (4 weeks) – Cyclophosphamide, cytarabine, 6- mercaptopurine Consolidation – 4-7 cycles of intensive multiagent chemotherapy – Delayed reinduction
MINIMAL RESIDUAL DISEASE Methods – Multicolor flow cytometry or PCR – Fusion transcripts – Rearranged immunoglobulin and T-cell receptor genes – Prognostic levels defined for children; prognostic Minimum Residualand levels yet toTime of Evaluation time points Disease PrognosisChildren At CR determined for adults< 0.01% Excellent outcome After CR > 0.1% High relapse risk
SENSITIVITY OF THE TECHNIQUES IN DETECTION OF MRDNO. TECHNIQUE SENSITIVITY1. MORPHOLOGY 1- 5%2. CELL CULTURE SYSTEM 10-1 – 10-33. CYTOGENETICS 10-1 – 10-3 FISH 10-3 DUAL COLOR / TRIPLE COLOR 10-4 INTERPHASE FISH 4 IMMUNOPHENOTYPE BY FLOW CYTOMETERY 10-3 MULTIPLE PARAMETER FLOW 10-4 – 10-5 CYTOMETERY5 SOUTHERN BLOT 1 – 5%6. PCR 10-3 – 10—4 RT – PCR 10-4 - 10-5 REAL TIME QPCR 10-6
PROGNOSTIC VALUE OF MRD IN ALL WHEN AND HOW OFTEN SHOULD MRD BE MONITORED SINGLE TIME POINT ANALYSIS IS INADEQUATE AT LEAST 2 SERIAL MEASUREMENTS ARE NEEDED DURING EARLY MONTHS OF TREATMENT1 AT END OF INDUCTION 1-RESPONSE TO TREATMENT2 AT START OF CONSOLIDATION-RISK OF RELAPSE IS PROPORTIONAL TO MRD LEVELS-POWERFUL PROG NOSTIC MARKER3 LOW RISK 10-3 INTERMEDIATE RISK 10-3 HIGH RISK 10-2 SLOWER KINETICS OF CLEARANCE IN T-ALL COMPARED TO PRE-B -ALL
CONSOLIDATION Hyper-CVAD is a dose-intensive regimen with alternating hyperfractionated cyclophosphamide and high doses of ara-C and methotrexate. CONSOLIDATION Compared with the earlier and less intensive regimen of vincristine, doxorubicin, and dexamethasone (VAD), CR rates (91% vs. 75%, P 0.01) and survival (P 0.01) were superior with hyper-CVAD
CONSOLIDATION In the CALGB 8811 study, patients underwent early and late intensification courses with eight drugs following a five- drug induction regimen. Maintenance therapy was given for 2 years after diagnosis. The median duration of disease remission was 29 months, and the median survival period was 36 months; these results were considerably better than those from earlier, less intensive trials.
CONSOLIDATION In the Medical Research Council(MRC) UKALL XA, patients were randomize to receive early intensification at 5 weeks, late intensification at 20 weeks, both, or neither. The early block of intensive treatment prevented disease recurrence although the DFS at 5 years was increased only slightly.
CONSOLIDATIONThe German multicenter trial 05/93 intensified the consolidation in a subtype-specific manner. In that study, patients received high-dose methotrexate for standard-risk B- lineage ALL, cyclophosphamide and ara-C for T-lineage ALL, and high-dose methotrexate and high-dose ara-C for high-risk B-lineage ALL.
CONSOLIDATION Induction was intensified with high- dose ara-C (4 doses of 3 g/m2) and mitoxantrone instead of the Phase II induction in high-risk patients. The CR rate was 87% for standard-risk patients, with a median duration of disease remission of 57 months and a 5-year survival rate of 55%. Intensified induction/consolidation did not improve the CR rate and DFS in high-risk patients, with the exception of pro-B ALL.
CONSOLIDATION The GIMEMA ALL 0288 study randomized patients to receive an early post-CR intensification versus maintenance therapy. Intensification of post- CR treatment did not influence the continuous CR rate.
CONSOLIDATION In the PETHEMA ALL-89 trial, patients in disease remission at the end of the first year were randomized to receive 16-week cycle of late intensification therapy. There was no difference in survival and DFS between patients who did or did not receive late intensification.
ADULT ALL: MAINTENANCE THERAPY Weekly methotrexate + daily 6- mercaptopurine – Monthly VCR/prednisone pulses Duration: 2-3 years Appropriate for all cases except B-cell and Ph+ ALL Poor outcome if omitted No randomized trials in adults
MAINTENANCE THERAPY Rationale: Long exposure to antimetabolite drugs will eliminate any subclones that persist after induction/maintenance Lasts 2-3 years after initial diagnosis Drugs – Daily 6-MP – Weekly oral methotrexate – Monthly vincristine, steroids – Periodic intrathecal chemotherapy
CNS DIRECTED THERAPYThe diagnosis of CNS leukemia requires the presence of more than five leukocytes per microliter in the CSF and the identification of lymphoblasts in the CSF differential. The presence of blasts in a CSF sample with less than five leukocytes per microliter may still signify CNS disease.
CNS DIRECTED THERAPY Measures of CNS prophylaxis include intrathecal (IT) chemotherapy (methotrexate, ara-C, steroids), high- dose systemic chemotherapy (methotrexate, ara-C, L- asparaginase), and craniospinal irradiation(XRT). The role of cranial XRT has becomecontroversial.
CNS DIRECTED THERAPYRisk factors for CNS leukemia in children include an age of 1 year or younger, excessive leukocytosis, T- lineage and mature–B-cell ALL, lymphadenopathy, thrombocytopenia, hepatomegaly, and splenomegaly.
CNS DIRECTED THERAPYMature–B-cell ALL, serum lactate dehydrogenase levels, and a high proportion of bone marrow cells in a proliferative state ( 14% of cells in the SG2M phase of the cell cycle) have been associated with a higher risk of CNS disease in adults
CNS DIRECTED THERAPY CNS prophylaxis consists of 4 IT treatments in the low-risk category, 8 IT treatments with high-risk disease, and 16 IT treatments for mature–B- cell ALL or Burkitt disease. Patients with cranial nerve root involvement may benefit from selective XRT to the base of the skull.
STEM CELL TRANSPLANTATION (SCT): CIMBTR RECOMMENDATIONS First CR – Allo SCT or MUD in high-risk patients – Role in standard-risk patients unclear but not recommended – Auto SCT: no benefit over chemotherapy Second CR – Allo SCT Hahn T, et al. Biol Blood Marrow Transplant. 2006;12:1-30.
ALL: SCT AT FIRST CRStudy Endpoint CHT Auto SCT Allo SCT Improved OutcomeCIBMTR vsGerman LFS 32% -- 34% NSstudiesJALSG 93 OS 40% -- 46% NSLALA 87 OS 35% 48% NSLALA 87 SR OS 45% 51% NSLALA 87 HR OS 20% 44% AlloLALA 94 HR OS 35% 44% 51% AlloGOELAL02 OS -- 40% 75% AlloHR
Allo BMT vs Auto BMT inPatients With Ph- ALL: MRC UKALL XII/ECOG E2993 High-Dose Sibling Allo BMT Methotrexate (n = 389) (3 doses) Patients with Ph- ALL aged < 55 yrs Yesin complete remission after HLA-matched sibling induction therapy donor available? (N = 919) No Auto BMT High-Dose Methotrexate (n = 530) (3 doses) Consolidation/Maintenance Chemotherapy: 2.5 yearsRowe JM, et al. ASH 2006. Abstract 2.
Allo BMT vs Auto BMT in Patients With Ph- ALL: 5- Year Results Improved OS with allo BMT vs auto BMT or postinduction chemotherapy in standard-risk Ph- patients – 5-year OS for allo BMT vs chemotherapy only: 54% vs 44%, respectively (P < .02) – No advantage in high-risk patients (younger than 34 years of age, WBC > 30,000 [B cell] or > 100,000 [T cell]) Outcome by Risk Group, % Donor No Donor P Value (n = 389) (n = 530) Overall 5-yr survival 53 45 .02 High risk 40 36 .50 Standard risk 63 51 .01 10-yr relapse rate High risk 39 62 < .0001 Standard risk 27 50 < .0001Rowe JM, et al. ASH 2006. Abstract 2.
Allo BMT vs Auto BMT in Patients With Ph- ALL: 5- Year Results (cont’d) Better EFS, OS with consolidation/maintenance chemotherapy vs auto BMT – No role for auto BMT in postremission Ph-negative ALL – Allo BMT treatment of choice in standard-risk patients Outcome by Risk Group, % Chemotherapy Auto BMT P Value Overall 5-yr survival 47 37 .06 High risk 40 32 .2 Standard risk 49 41 .2 Overall EFS 42 33 .02Rowe JM, et al. ASH 2006. Abstract 2.
TRANSPLANT IN PH- ALL Conflicting data about allo SCT in CR1 French LALA-87 – 46% vs 31% 10-year survival in transplant vs. chemotherapy (p=0.04) – High risk patients derived most benefit from transplant • Ph+ • Age > 35 • WBC > 30,000 • Time to CR > 4 weeks – Standard risk patients had comparable benefit 49% vs. 39% survival (p=0.6)
TRANSPLANT IN PH- ALL French LALA-94 – High risk and patients with CNS involvement did better with transplant – Results confirm earlier LALA-87 trial
TRANSPLANT IN PH- ALL MRC UKALL12/ECOG 2993 Study – Largest prospective trial enrolling 1913 patients between 1993 and 2006 – All patients younger than 50 (later 55) with a matched sibling donor were assigned to transplant – Ph+ patients were assigned to MUD transplant if no matched sib were available – High risk • Age > 35 years • WBC > 30,000 (or >100,000 for T-cell disease) • Ph+ status
Transplant in Ph- ALL Overall survival was 53% for patients with donor vs 45% for those without (p=0.01) Standard risk patients derived the most benefit, 62% vs. 52% 5-year overall survival High risk patients did not have differing outcomes (41% vs. 35%, p=0.2) Why? – Maybe transplant is better – Maybe TRM was higher in older patients
Autologous SCT Multiple studies incorporated auto transplant for patients without donors None showed a benefit of auto SCT versus chemotherapy No consistent role for auto SCT as a treatment for ALL
Relapsed Disease Requires multi-agent treatment to re-induce a remission Consolidate with transplant if possible Nelarabine for T-cell disease Very poor prognosis overall