POST REMISSION THERAPY IN ALL

DR. R. RAJKUMAR III YR POST GRADUATE DEPARTMENT 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

2004TREATMENT – 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 lasting for several months (reported 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 (Karon, Freireich and Frei)

2004DISCOVERY 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

2004

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

2004

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, toxicity, pessimism

2004

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 Objective - CURE

2004

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– Dramatic improvement - 50% long term

survival

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

Over a period of months

2-3 years

CNS Prophylaxis (IT-MTX)

Induction, consolidation, maintenance phases– CNS prophylaxis with IT-MTX

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 time points and levels yet to determined for adults

Time of Evaluation Minimum Residual Disease Prognosis

Children

At CR < 0.01% Excellent outcome

After CR > 0.1% High relapse risk

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 INTERPHASE FISH

10-4

4 IMMUNOPHENOTYPE BY FLOW CYTOMETERY 10-3

MULTIPLE PARAMETER FLOW CYTOMETERY

10-4 – 10-5

5 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 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

INCTR 2004

INCTR 2004

INCTR 2004

CONSOLIDATION

INCTR 2004

CONSOLIDATION

INCTR 2004

INCTR 2004

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.

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.

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

INCTR 2004

INCTR 2004

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.

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 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.

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

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 CR

Study Endpoint CHT Auto SCT Allo SCT ImprovedOutcome

CIBMTR vs German studies

LFS 32% -- 34% NS

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 HR OS -- 40% 75% Allo

Allo BMT vs Auto BMT in Patients With Ph- ALL: MRC

UKALL XII/ECOG E2993

Rowe JM, et al. ASH 2006. Abstract 2.

Patients with Ph- ALL aged < 55 yrs

in complete remission after induction therapy

(N = 919)

Sibling Allo BMT(n = 389)

High-Dose Methotrexate

(3 doses)

HLA-matched sibling donor available?

Yes

High-Dose Methotrexate

(3 doses)

Auto BMT

Consolidation/Maintenance Chemotherapy:

2.5 years

(n = 530)

No

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(n = 389)

No Donor(n = 530)

P Value

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.

Allo BMT vs Auto BMT in Patients With Ph- ALL: 5-

Year Results (cont’d)

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.

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

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

INCTR 2004

INCTR 2004

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