This document summarizes the history and treatment of leukemia. It describes key discoveries such as the initial descriptions of leukemia in 1845 and the development of early treatments using arsenic and radiation in the late 19th/early 20th centuries. It then summarizes the modern era of treatment, including the use of chemotherapy drugs discovered in the 1940s-1960s, the development of combination chemotherapy, and the total therapy approach developed at St. Jude involving induction, consolidation, and continuation phases. It discusses principles of treatment such as the need for post-remission therapy, CNS prophylaxis, and monitoring of minimal residual disease.

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

17. INCTR
2004

18. INCTR
2004

19. INCTR
2004

20. CONSOLIDATION
INCTR
2004

21. CONSOLIDATION
INCTR
2004

22. INCTR
2004

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

32. INCTR
2004

33. INCTR
2004

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

50. INCTR
2004

51. INCTR
2004

52. Emerging Treatment Options
 Nelarabine
 Clofarabine
 Liposomal vincristine
 Newer TKIs
 Alemtuzumab (Campath)
 Blinatumumab (BiTE antibody)
– CD19 and CD3 antibody that brings cytotoxic
T cell into proximity with B-cell ALL cell