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Post remission therapy in all symposium
1. POST REMISSION THERAPY
IN ALL
DR. R. RAJKUMAR
III YR POST GRADUATE
DEPARTMENT OF MEDICAL ONCOLOGY
2. 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
3. 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
4. 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)
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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 to
Time of Evaluation
time points Disease Prognosis
Children
At CR determined for adults< 0.01% Excellent outcome
After CR > 0.1% High relapse risk
15. SENSITIVITY OF THE TECHNIQUES IN
DETECTION OF MRD
NO. TECHNIQUE SENSITIVITY
1. MORPHOLOGY 1- 5%
2. CELL CULTURE SYSTEM 10-1 – 10-3
3. 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
CYTOMETERY
5 SOUTHERN BLOT 1 – 5%
6. PCR 10-3 – 10—4
RT – PCR 10-4 - 10-5
REAL TIME QPCR 10-6
16. 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 TREATMENT
1 AT END OF INDUCTION 1-RESPONSE TO TREATMENT
2 AT START OF CONSOLIDATION-RISK OF RELAPSE IS
PROPORTIONAL TO MRD LEVELS-POWERFUL PROG NOSTIC
MARKER
3 LOW RISK 10-3 INTERMEDIATE RISK 10-3
HIGH RISK 10-2
SLOWER KINETICS OF CLEARANCE IN T-ALL COMPARED TO
PRE-B -ALL
23. 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
24. 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.
25. 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.
26. CONSOLIDATION
The 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.
27. 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.
28. 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.
29. 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.
30. 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
31. 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
34. CNS DIRECTED THERAPY
The 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.
35. 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 become
controversial.
36. CNS DIRECTED THERAPY
Risk 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.
37. CNS DIRECTED THERAPY
Mature–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
38. 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.
39. 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.
40. ALL: SCT AT FIRST CR
Study Endpoint CHT Auto SCT Allo SCT Improved
Outcome
CIBMTR vs
German LFS 32% -- 34% NS
studies
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
OS -- 40% 75% Allo
HR
41. Allo BMT vs Auto BMT in
Patients 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 Yes
in 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 years
Rowe JM, et al. ASH 2006. Abstract 2.
42. 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 < .0001
Rowe JM, et al. ASH 2006. Abstract 2.
43. 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 .02
Rowe JM, et al. ASH 2006. Abstract 2.
44. 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)
45. TRANSPLANT IN PH- ALL
French LALA-94
– High risk and patients with CNS
involvement did better with transplant
– Results confirm earlier LALA-87 trial
46. 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
47. 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
48. 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
49. 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