LEUKEMIA

AML
APL
ALL
CML
CLL
HCL

AML

General Discussion, Genetics, Elderly Patient, Chemotherapy

 

GENERAL DISCUSSION OF AML

EPIDEMIOLOGY

A.Genetic Syndromes

Congenital - Down's, Fanconi's, Klinefelter's, neurofibromatosis

Acquired - myeloproliferative, aplastic anemia, PNH, MDS

B.Environmental Factors: Benzene (shoe factory), Ionizing radiation, Thoratrast (less common now), smoking - some studies, Drugs (Alkylating agents, Radiation + chemotherapy in HD, Other chemotherapy agents: CDDP, VP16, Analgesics [phenylbutazone], Chloramphenicol, chloroquine)

PRESENTATION

A.Symptoms

Nonspecific Fatigue - most common complaint. Usually present for several months.

Pallor

Fever - 15-20%

Bleeding, petechiae, epistaxis - up to 1/2

Wt loss - 50%

Bone pain - < 20%

Skin and gum infiltration

CNS involvement - uncommon, but in M5 and hyperleukocytosis

LAB

WBC - varies widely. > 50% have WBC. Only 20% have WBC > 100K.

Neutropenia - most patients

Anemia

Thrombocytopenia - production, DIC

uric acid

lysozyme (esp M4 and M5) renal tubular damage and K

Hyperleukocytosis risk or CNS, lung, and GU involvement (including testicle)

DIFFERENTIATING AML FROM ALL

Morphology

Auer rods and Phi bodies

Special stains (myeloperoxidase = AML, TdT = ALL, but see crossover in 5-10%)

Flow cytometry - mixed lineage in up to 20%

FAB CLASSIFICATION

CYTOGENETICS

Abnormal chromosomes are probably present in all patients with AML Can detect abnormalities in 50-70%. Important to try both for treatment and prognostic purposes

t(15;17) - virtually diagnostic of M3 type (APL) which has different treatment and better prognosis

inv(16) - associated with marrow eosinophilia. Has better prognosis, but tends to have higher risk of CNS relapse.

t(8;21) - M2 - usually children or young adults. Higher incidence of splenomegaly and chloromas. Associated with Down's. High CR rate.

The more abnormalities, the greater the chance of relapse and, therefore, the worse the prognosis. Thus need to treat more aggressively, if possible.

BAD PROGNOSTIC FACTORS

Clinical

Age < 2 or > 60
WBC > 100K
CNS Disease
Difficulty inducing remission

Morphology

No Auer rods
No eos in BM
Megaloblastic erythroid changes
FAB types M5, M6, M7

Phenotype

CD34+
HLA-DR+
TdT+ (in AML)
Biphenotypic markers

 

ALL

Facts, FAB Criteria,
Chemotherapy: (CALGB, Hoelzer, Sloan-Kettering, Hyper-CVAD)
Relapsed: Chemo

POOR PROGNOSTIC FACTORS

WBC > 25-30K
Ph+
Bulky disease
Pure B-cell
>4weeks to CR
Adult age

CYTOGENETICS

t(9;22) Ph+
t(4;11) Mixed lineage - poor prognosis
t(1;19) Pre-B - poor prognosis
t(8;14) Pure B
t(11;14) T-cell

Ph+ ALL
25% adults / 5% kids
Usually non-T, non-B cell ALL
Never found in T-cell ALL (may be why T-cell ALL has better prognosis)
Usually older adults
May appear as blast crisis from CML

Ph+ product in ALL is different from CML, which allows one to distinguish whether originated from CML or de novo

IMMUNOPHENOTYPE

- 80% of adults early B (CD19, 20+). Most also express CALLA (CD10).

- B-cells that are + or - for CD10 are all called "early pre-B ALL" (TdT+).

- "Null" - lacks CD10

- "Pre-B" - cytoplasmic heavy chains

- "B-cell ALL" - IgM on surface. These patients express strong CD20 and CD37. They do NOT express TdT like other ALLs. Morphologically resemble L3.

- "T-cell ALL" - 20% adults; CD3+, CD7+; phenotype determined by TCR gene rearrangement

Lymphoid stem cell (TdT+, CD34+) --> Early pre-B (TdT+, HCR) --> Pre-B (TdT-,CytoHC) --> Immature B (Cyto LC) --> Mature (SigM)

Exposure to Ag --> "activated B": expresses CD25 (IL-2R), CD23 (IgE-R)

 

ALL: CALGB REGIMEN FOR ADULTS (This regimen was used in CALGB 8811 [Larson et al in Blood 85:2025 4/95] and also in CALGB 9111 [Larson et al Blood 92:1556, 9/98]. The latter study added G-CSF and found that it made no significant difference.) This regimen is still recommended for ALL and lymphoblastic lymphoma in UpToDate as of July 2005. For aggressive lymphomas (lymphoblastic or Burkitt’s, one may also use Hyper-CVAD or CODOX-M (for low risk Burkitt’s).

Induction, Early Intensification, CNS Prophylaxis, Late Intensification, Maintenance

Course 1: Induction (4 weeks)

CTX    1200 mg/m2     IV        Day 1
DNR    45 mg/m2        IV        Day 1,2,3
VCR    2 mg                IV        Days 1,8, 15,22 (weekly)
Pred     60 mg/m2/d     IV/po Days 1-21
L-Asp 6000 u/m2         SQ       Days 5, 8, 11, 15, 18, 22 (biweekly)

(Use cryo to keep Fibrinogen >100)

For patients >= 60yo, reduce these as follows:

CTX    800 mg/m2      IV        Day 1
DNR    30 mg/m2        IV        Day 1,2,3
Pred     60 mg/m2/d     Day 1-7

Course 2: Early Intensification
(4wk, repeat once)

IT MTX           15 mg               Day 1
CTX    1000 mg/m2     IV Day 1
6-MP 60 mg/m2/d po   Day 1-14
Ara-C 75 mg/m2/d SQ Days 1-4, 8-11
VCR    2 mg    IV        Day 15,22
L-Asp 6000 u/m2         SQ       Days 15, 18, 22, 25

Course 3: CNS Prophylaxis and Maintenance (12wk)

Cranial RT        2400 cGy         Day 1-12

IT MTX 15 mg Days 1, 8, 15, 22, 29 (weekly x 5)

6-MP 60 mg/m2           PO       Day 1-70
MTX 20 mg/m2           PO       Day 36, 43, 50, 57, 64

Bactrim for PCP prophylaxis given during course 3.

Course 4: Late Intensification (8 wk)

DOX    30 mg/m2        IV        Day 1, 8, 15
VCR    2 mg    IV        Day 1,8,15
Dex      10 mg/m2/d PO           Day 1-14
CTX    1000 mg/m2     IV        Day 29
6/TG    50 mg/m2        PO       Day 29-42
Ara-C 75 mg/m2          SQ       Day 29-32, 36-39

Course 5: Maintenance (until 24 months from Dx)

VCR    2 mg    IV        Day 1 every 4 wk
Pred     60 mg/m2/d PO           Day 1-5 every 4 wk
MTX    20 mg/m2        PO       Day 1, 8, 15, 22
6-MP 60 mg/m2/d PO Day 1-28

 

ALL: FAB (Adults)

L1 - Small, homogeneous, high N:C ratio, small nucleoli (20% incidence, 85% CR, 40% 3y DFS)

L2 - Larger, pleomorphic, low N:C ratio, prominent nucleoli (70, 75, 36)

L3 - Large, vacuolated basophilic cytoplasm, large vesicular nucleus, large nucleoli (10, 65, 10)

 

ALL: HOELZER REGIMEN (ADULTS) (Blood 71,123 1/88)

Induction

Phase1

Prednisone       60 mg/m2 po d 1-28
Vincristine        1.5 mg/m2 IV d 1,8,15,22
Daunorubicin    25 mg/m2 IV d 1,8,15,22
L-asparaginase 5000 U/m2 IV d 1-14

Phase 2

CTX    650 mg/m2 IV* d 29, 43, 57
Ara-C 75 mg/m2 IV d 31-34, 38-41, 45-48, 52-55
6-MP 60 mg/m2 po      d 29-57

MTX    10 mg/m2 IT** d 31, 38, 45, 52

Reinduction

Phase 1

Decadron 10 mg/m2 po d 1-28
Vincristine 1.5 mg/m2 IV 1,8,15,22
DOX    25 mg/m2 IV    d 1, 8, 15, 22

Phase 2

CTX    650 mg/m2 IV* d 29
Ara-C 75 mg/m2 IV d 31-34, 38-41
Thioguanine 60 mg/m2 po         d 29-42

Maintenance

6-MP 60 mg/m2 po QD weeks 10-18 and 29-130

MTX 20 mg/m2 po/iv weekly weeks 10-18 and 29-130

----------------

* Max single dose = 1000mg
** Max single dose = 15mg

See article for RT recommendations.

CR achieved in 74% of 368 patients. CR obtained within 4 weeks in 60%. 14% needed phase II of induction. Lower CR rate in patients with bleeding at diagnosis, splenomegaly, or hepatomegaly. T-ALL had higher RR than c-ALL or null-ALL. Only 1 with B-ALL got CR.

 

ALL: SLOAN-KETTERING (JCO 14:2480-2485 9/96)

Induction

Ara-C 3g/m2/d IV/3h days 1-5 (remember eye drops)

Mitoxantrone 80 mg/m2 IV day 3 only

G-CSF 200mcg/m2/d IV/4h start day 7 until ANC > 5.0

IT-MTX 6 mg/m2 days 1, 4

Consolidation A

Pred     60 mg/m2/d given TID x 30d, then taper over 10d.

Bactrim day 30 through 1 wk post taper

VCR    2 mg/m2 (age <60 max 4mg; >60 max 2.5mg). Give every 10 days x 5 starting day 1

MTX    Day 10 -- 80 mg/m2
            Day 20 --110 mg/m2
            Day 30 --140 mg/m2
            Day 40 --170 mg/m2

L-Asp 10,000 IU/m2 IV days 1, 11, 21, 31, 41

IT-MTX 6 mg/m2 (15mg max) days 10, 20, 30, 40

Patients in CR have Ommaya placed between Consol A and B

Consolidation B

Etop     200 mg/m2 IV/1h days 1,2,3

Ara-C 25 mg/m2 IVB, then 200 mg/m2 CIV days 1-4

G-CSF 200 mcg/m2 SQ QD day 6 until ANC > 5.0

See article for maintenance.

 

AML CHEMOTHERAPY 

Induction: Ida 7+3, DNR 7+3, Mitoxantrone, HiDAC

Consolidation: Mayer, HiDAC (Cassileth), MDACC (for elderly patients)

Prognosis with Treatment

 

AML: ELDERLY PATIENTS
(Blood 96:1670, 9/00)

In patients > 55yo, CR rates ~ 50%, but usually transient lasting < 12 months. Less than 10% chance of remaining in CR for 3 yrs.

However, some patients may depart significantly from the average (ie, good prognostic features). In those, CR may be up to 72% (age 55-65 and o/w normal), with MS 1.5 yrs and 3YS 15%.

ADVERSE PROGNOSTIC FEATURES:

Age >= 65
Performance status >2
Bili >2
Cr >2
Abnormal cytogenetics (excluding inv 16, t(8;21))
Secondary AML
MDR1 expression

APPROACH:

1. Age 55+:

No adverse factors --> 7+3
1+ factors --> go to 2.

2. Age 65+:

Performance 3+ or age > 80 --> investigational or palliative care

Performance 0-2 and age < 80, --> go to 3.

3. Cytogenetics:

Highly abnormal (-5/-7, complex), or secondary AML or + MDR expression --> investigational, possibly omitting Ara-C.

Less abnormal (eg +8) or secondary AML or MDR expression only --> investigational including Ara-C.

If investigational not available, then palliative care vs standard, depending upon case.

 

AML: GENETIC CLASSIFICATION

Gene Defect(Freq%) - Clin Lab - (%CR) (%Durable CR)

Inv(16) or del(6) - (5%) M4Eo; often high WBC; chloromas; AraC sens; (>90%) (40-50%)

t(8;21) - (5%-10%) Auer rods, tends to be M2; low WBC; AraC sens; (>90) (30-40%)

t(15;17) - (5-10%) M3; hyper- or hypogran; DIC; low WBC; ATRA or anthracyclines (70%) (40%)

-5, 5q-, -7, 7q- (20%) Often assoc w preceding MDS or prev alkylator tx; older patients; Auer rod neg. (30-50%) (<5%)

+8 (15%) Assoc w MDS; older patients (40-65%) (<5)

20q- (<5%) MDS; older patients (<50%) (<5%)

11q (5%) In kids, assoc w CNS involvement; assoc w prior tx w topo-II drugs (50-80%) (<10%)

Misc [abnl 3q] (5-10%)t(6;9), assoc w basophilia & thrombocytosis (50-75%) (<10%)

Insuff metaphases (5-10%) - (50-80%) (<10%)

None (30%) - (50-80%) (20-25%)

-----------------------

The chance of relapse decreases sharply after 2yrs of remission, then continues to decrease.

 

AML: INDUCTION CHEMO

Idarubicin 7+3

Ara-C 100 mg/m2/d CIV d1-7
Idarub 12 mg/m2/d IVB d1-3

If day 14 BM shows residual leukemia, treat with 5+2 using Ida.

Standard 7+3

Ara-C 100 mg/m2/d CIV d1-7
DNR    45 mg/m2/d IVB d1-3

If day 14 BM shows residual leukemia, treat with 5+2.

Mitoxantrone

Ara-C  100 mg/m2/d CIV d1-7
DHAD 12 mg/m2/d IVB d1-3

If day 14 BM shows residual leukemia, treat with 5+2 using DHAD.

Hi-DAC

2-3 gm/m2 IV/1 hr q12h x 8-12 doses.

Use steroid eyedrops q6h until 24h after chemo complete.

Monitor for cerebellar dysfunction.

 

AML: INDUCTION/CONSOLIDATION
(Mayer, NEJM 331:896, 10/94)

INDUCTION:

Ara-C 200 mg/m2/d CIV x 7 days
DNR 45 mg/m2 IVB days 1,2,3

(For age > 60, 30 mg/m2 dose)

- If Day 14 marrow shows > 5% blasts or if >15% cellular, then give 5+2.

CONSOLIDATION:

Age <= 60:

Ara-C 3 gm/m2 IV/3 hrs q 12 h (twice daily) on days 1,3,5

Repeat q 4 weeks x 4 cycles

With this regimen, probability of remaining in remission after 4 years = 44%.

Age > 60:

Ara-C 100 mg/m2/d CIV x 5 days
Repeat q 4 weeks x 4 cycles.

(MDACC uses 1 gm/m2 q12h days 1, 3, 5 x 4 courses and does not use maintenance)

MAINTENANCE:

Ara-C 100mg/m2 SQ q12h x 5 days
DNR 45 mg/m2 IV day 1

Repeat q 4 weeks x 4 (Maintenance was dropped from later trials because it did not show a clear benefit, but some still use it.)

PROGNOSIS IN MAYER'S STUDY
Results of induction therapy:

Age < 40 75% CR
Age 40-60 68% CR
Age > 60 47% CR

4 Year DFS:

Age < 40 32%
Age 40-60 29%
Age > 60 14%

 

CLL

Staging, Prognosis, Chemotherapy (Initial, Salvage)
PLL

 

CLL CHEMO

Rituxan/Cytoxan/Fludarabine

As used for Low-grade Lymphoma. Click here to see.

Fludarabine

25 mg/m2/d x 5 days every 4 weeks up to 1 yr.

If stays in CR or PR > 12 months, can usually retreat if need to.
74% RR in chemotherapy-naive patients.
50% RR in previously treated patients.

Chlorambucil (Leukeran)

Pulse   20-30 mg/m2 d1, q2-4wk (2mg tabs)

Continuous 2-5 mg/m2 QD

Prednisone 20-40 mg/m2/d days 1-5 every 2-4 weeks may be combined with either pulse or continuous chlorambucil. RESERVE FOR PATIENTS WITH AUTOIMMUNE SXS OR PHENOMENA.

CVP

CTX    300 mg/m2 PO d 1-5
VCR    2 mg IV d 1
Pred     100 mg/m2 po d 1-5

Repeat q3-4wk

75% RR (25% CR)

Randomized trials have NOT demonstrated any benefit over single-agent chlorambucil.

 

Salvage Chemotherapy for CLL:

HD Rituxan
(JCO 19:2153 4/01).

Day 1: Rituxan 100 mg/4 hrs (25 mg/hr)
Day 3: Rituxan 375 mg/m2 at 50 mg/hr, then increase by 100 mg/hr every 30 min to maximum of 400 mg/hr.
Day 5: 375 mg/m2 at 50 mg/hr rate x 15 min, then increased to administer entire dose over 1 hour thereafter.
Repeat Day 5 dose 3 times/week for 3 weeks (4 weeks total therapy).

Premed: Benadryl 50 mg IV and Tylenol 650 mg po 30 min prior.

Overall RR = 45% (3-CR, 42-PR). Median duration = 10 months. Small study.

RCD
(Proc ASCO #1133)

Rituxan 375 mg/m2 day 1
Cyclophosphamide 750-1000 mg/m2 day 2
Decadron 12 mg po days 1-7
Repeat q 4 weeks to maximum response.

After a median of 4 cycles (range 2-8), 36% had achieved CR and 41% a PR. Median duration was 7 months. Minimal toxicity. Criticism: Small study.

 

Miscellaneous:

Alemtuzumab (Campath)- approved for patients who fail fludarabine.

Chlorambucil 20-30 mg/m2 q2 weeks. (2mg tabs)

 

CLL: STAGING

O - Lymphocytosis-15,000/mm3; marrow 40% lymphs (12.5 yr MS)  

I - Lymphocytosis + adenopathy (9.5 yr MS)

II - Lymphocytosis + hepato- or spleno-megaly (8 yr MS)

III - Lymphocytosis w anemia (Hb < 11 or Hct < 33) [adenopathy/hepato- splenomegaly may or may not be present) (1.5 yr MS)

IV - Lymphocytosis w thrombocytopenia < 100K (1.5 yr MS)

 

CML CHEMO

Gleevec (imatinib, STI571)

Indicated in patients who fail IFN.
Chronic phase: 400 mg qd
Accelerated Phase or Blast Crisis: 600 mg qd
Supplied: 100 mg caps. Take with food and large glass of water.

IFNa-2a

Start 2 mu/m2 SQ TIW. If able, gradually increase to 5 mu/m2 qd.

Induces hematologic CR in 70-80%, and cytogenetic response in 40-60%. (CR = 0% Ph+, PR = 1-34%, Minor = 35-90%). Median time to major cytogenetic response is 18-22 months.

Early side effects:

Flu-like sxs - last 3-4 weeks

Late side effects:

Persistent fatigue, Wt loss, Depression (can be helped with antidepressant)

Immune-mediated side effects: Hypothyroidism, Collagen vasc disorders, Thrombocytopenia, Organ dysfunction (CHF, CRF)

 

Hydrea

500-1500 mg/m2 (1-5gm qd)

For CML: 40 mg/kg/d until WBC <50K, then reduce by 50%. Then adjust to keep WBC between 2-8K.

1-5 gm/d x 5-10d intermittently to maintain WBC 10-50K OR 0.5-2.0 gm/d continuous to keep WBC 2-5K

Drug of choice in patients who are candidates for BMT. Both busulfan and hydrea --> hematologic remission rates of 70-80% in chronic phase. (Ph+ chromasome persists in > 90%). Thus, these drugs offer effective dz control & prolong survival, but do not prevent transformation.

Busulfan

4-8 mg po qd x 5 or until WBC <=15 OR

2-8 mg po qd x 5-10d or until WBC 20 (MKSAP)

Affects an earlier stem cell and provides longer control than hydroxyurea. However, associated with unpredictable prolonged myelosuppression in 10%, and with occasional fibrosis of lungs/heart/BM, and Addison's dz. Used in older patients who are not BMT candidates. (Patients who get busulfan before BMT have worse outcome than patients who are txd with Hydrea.)

 

CML

Prognosis, Treatment, Chemo

 

CML PROGNOSIS

With IFN, Med Surv --> 7yrs

If good risk and can get cytogentic response, MS = 9 yrs and 85% alive at 6-8 yrs.

With IFN/AraC, hematologic RR = 90%, cytogenetic RR = 70%. Major RR > 50%, and CR in 30%.

IFN/AraC/homoharringtinine --> ?

 

CML TREATMENT FACTS
(Kantarjian, Blood 87:3069, 4/96)

Most patients (75-80%) are not candidates for related (match or 1 antigen mismatch) alloBMT. In this group, an initial trial of IFN-a is indicated. Patients who achieve complete hematologic response (CHR-defined as complete normalization of counts and spleen return to normal) by 6-8 mon and a cytogenetic response (Ph chrom neg) by 12 mon may cont the IFN tx as long as the cytogenetic response persists or for at least 3yrs in cytogenetic CR (Ph chrom 0%).

Patients who do not achieve cytogenetic response after 12 mon may either continue IFN-a tx or be offered investigational approaches aimed at suppressing Ph+ dz.

May take 8 mon to find a MUD donor, and even longer in blacks or Orientals, so preliminary MUD search may need to start soon after dx.

Patients with matched donor may be offered alloBMT initially or after a trial of IFN based on pt age, preferences, & experience with alloBMT and IFN. In general, younger patients may undergo alloBMT as init tx if risk of the procedure is low (<20% 2yr mortality) or if the experience with IFN-a in terms of achieving cytogenetic response is poor. Older patients or with expected txplant mortality >20% may undergo init IFNa therapy and would have alloBMT if no response is observed after 12 mon or if relapse.

In general, better to txplant early chronic phase (< 12 months from dx) rather than late.

 

HAIRY-CELL LEUKEMIA

Treatment Indications
Observation
Response Criteria
Chemotherapy
Splenectomy

INDICATIONS FOR TREATMENT:

Symptomatic splenomegaly
Hb < 10
Plt < 100
WBC > 20
ANC < 1000
Autoimmune complications
Tissue infiltration with HCs
Recurrent infections

RESPONSE CRITERIA

CR:

Hb > 12
ANC > 1.5
Plt > 100
No transfusion requirement
No HCs in marrow (standard morphologic review)
Regression of splenomegaly

Partial Responses require reduction of the hairy cells in the bone marrow to < 50%, < 5% hairy cells in PB, >50% reduction in the organomegaly, and normalization of the CBC.

Minimal Response requires the normalization of at least one of the PB cell elements and decrease of the PB circulating cells by at least 50%.

OBSERVATION

A small group of patients having an indolent course can be observed without any treatment. In general, in patients with one or two cytopenias without any other symptoms and not requiring transfusion, observation is a reasonable approach. Only 2% of HCL patients belong to that category. Few cases of spontaneous remission of HCL have been reported.

SPLENECTOMY

Splenectomy is no longer front-line treatment in patients with HCL and is reserved for patients with splenic rupture, infarcts, massively enlarged spleens, severe hypersplenism, or failure to systemic chemotherapy.

CHEMOTHERAPY

2cda (Cladribine, Leustatin)
Pentostatin
Fludarabine
IFNa

Interferon-Alfa (Ifn-Alfa)

Multiple studies have been conducted using natural and recombinant IFN-alfa at doses of 3 million U/d by IM or SC injections for 6 months, followed by 3 million U/d three times a week for 12 or 24 months. The overall results in 10 different studies and a total of 417 HCL patients were evaluated by Jaiyesimi and colleagues. The CR rate was 8%; PR rate, 74%; and rate of no responses, 8%. The median time to response was 6 months for patients achieving PR and 14 months to achieve CR. Patients frequently relapsed between 12 and 24 months after discontinuation of therapy. Reinduction with IFN-a was successful in most previous responders.

PURINE ANALOGS

Pentostatin is a purine analog that binds to adenosine deaminase (ADA). The recommended dose is 4 mg/m2 IV bolus every other week until a CR is obtained. Usually, patients require a median of 8 courses (range, 4 to 15). The CR rate varies between 59% and 89% in different studies, and the PR between 4% and 37%. Responses can last for many years, and patients who relapse often respond to retreatment with pentostatin.

Cladribine (Leustatin) is an active drug for the treatment of HCL, achieving similar activity to pentostatin. Due to this and the advantage of one cycle of a 7-day infusion, this drug is sometimes the first choice for treatment of this disorder. Intracellular accumulation of 2-chloro-deoxy ATP inhibits ribonucleotide diphosphate reductase, which inhibits DNA synthesis. In addition, inhibition of DNA polymerase and DNA ligase prevents DNA repair, resulting in increased DNA strand breaks, which, in turn, may accelerate the process of apoptosis. The largest clinical trial was performed by Piro and colleagues, who treated 144 HCL patients with cladribine, 0.1 mg/kg/d by continuous IV infusion for 7 days. A total response rate of 97% was obtained, with 85% CR and 12% PR rates. The response was independent of previous treatment with IFN or splenectomy, and three patients refractory to pentostatin were responsive to cladribine. With a median follow-up of 14.2 months (range, 8.1 to 68.3 months), only four patients relapsed. Recovery of blood counts occurred by day 61 (range, 11 to 268 days). At M.D. Anderson, Estey et al treated HCL patients and noted a 78% CR rate, 11% PR rate, and one minimal response. Four HCL patients who relapsed after responding to cladribine were retreated again with the same drug, resulting in two CRs and one PR.

OTHER TREATMENTS

There is very limited clinical data on the use of fludarabine in HCL. Kantarjian et al treated three patients (two with HCL and one with HCL variant), observing two PRs. Some patients occasionally responded to chlorambucil, cyclophosphamide, and combination chemotherapy.

 

PROLYMPHOCYTIC LEUKEMIA (VS CLL)
(Williams)

CLL

Morphology: small "resting" LCs w dense chromatin and "smudge" cells.

Immuno: Sig low density; CD5+ 95%, CD20 +, CD22 +

5% have M-spike. Blood LC count usu < 100. Anemia or thrombopenia < 25%. Lymphadenopathy common.

PLL

Morph: Large LCs (10-15 microns) with open chromatin and prominent nucleoli

Immuno: Sig 50%. CD20 +++, CD22 +++

> 30% have M-spike. Massive splenomegaly. >80% have anemia or thrombopenia. Mild lymphadenopathy, if any.

Clinical Features and Prognosis:

Subacute lymphoid leukemia with incidence ~10% that of CLL.

May evolve from B-cell CLL.

14q+ abnormality in 60%. Trisomy 12 less than CLL.

20% are T-cell PLL expressing CD2 and CD4.

Massive splenomegaly in 2/3

Usually minimal lymphadenopathy

1/3 have infiltration of skin, arms, face nonscaling, papular, nonpruritic rash.

Often anemic (N/N) and plts <100K

3/4 have LC count >100K

BM diffusely infiltrated w prolymphocytes

Like CLL, hypogammaglob common, but 1/3 have M spike

Chlorambucil, CHOP, CTX used. Usually short response.

Purine analogues effective, but limited experience.

Splenic RT or splenectomy may ameliorate symptoms temporarily.

IFNa in some, but usually less effective than chemo

Med survival 3yrs (vs 8yrs for CLL). Patients with T-cell PLL even worse: 6-7mon.

 

HiDAC for AML Consolidation
(Cassileth, NEJM 339:1649, 12/98)

Showed HiDAC to be as good as BMT. The Ara-C is given for 12 doses, not the usual six.

The study has been criticized because of its intention-to-treat design. Only 81% of alloBMT and 54% of autoBMT patients actually completed therapy whereas 91% of HiDAC patients did. This potentially favors the HiDAC group.

First consolidation course: Ida 12 mg/m2 x 2 days plus Ara-C 100 mg/m2 CIV x 5 days (5+2)

Then: Ara-C 3 gm/m2 IV/3 hours q 12h x 12 doses (6 days)

4YS for patients 55 and younger:
AlloBMT    46%
AutoBMT  43%
HiDAC      52%

Hyper-CVAD for Adult ALL (JCO 18(3):547, 2/00)

(Kantarjian et al, MDACC)

 

The Hyper-CVAD and HD MTX-Ara-C are given for 8 courses (4 each) in the Dose Intense phase as follows:

 

Hyper-CVAD: (courses 1,3,5,7)

Cytoxan 300 mg/m2 IV/3 hours q 12 hours x 6 doses days 1-3

Mesna 600 mg/m2/day CIV/24 hours days 1-3 (Start with Cytoxan and end 6 hours after last dose)

VCR 2 mg IV days 4 and 11

Doxorubicin 50 mg/m2 IV day 4

Decadron 40 mg QD days 1-4 and 11-14

 

HD MTX-Ara-C: (courses 2,4,6,8)

MTX 200 mg/m2 IV/2 hours followed by 800 mg/m2 IV over 24 hours day 1

Leucovorin – Start 24 hours after completion of MTX infusion. Start with 15 mg IV q 6h x 8. Increase to 50 mg q6h if MTX levels are more than 20 umol/L at the end of the infusion, more than 1 umol/L 24 hours later, or more than 0.1 umol/L 48 hours after the end of the MTX infusion, until levels are lower than 0.1 uM

Ara-C 3 gm/m2 IV/2 hours q 12h x 4 days 2 and 3

Methylprednisolone 50 mg IV BID days 1 thru 3

 

CNS Prophylaxis:

Give if pure B-cell (high risk), LDH > 2.5 x normal (high risk) or if risk unknown.
MTX 12 mg IT day 2 and

Ara-C 100 mg IT day 8 of each cycle for 16 IT treatments in high risk, 4 IT treatments in low risk, and 8 treatments in unknown risk.

If known disease, treat twice weekly until CSF negative, then according to protocol.

 

Prophylactic Antibiotics:

Given during dose-intense phase:

Cipro 500 mg BID or Levaquin 500 mg QD

Diflucan 200 mg po QD

Acyclovir 200 mg QD or Valacyclovir 500 mg QD

 

Supportive care:

G-CSF 5 mcg/kg BID starting 24 hours after end of chemotherapy (day 5 of Hyper-CVAD and day 6 of HD MTX-Ara-C).

 

Timing:

Subsequent courses given as soon as WBC > 3 and platelet count > 60. Neupogen not interrupted if platelet recovery delayed unless WBC is >30K.

 

Adjustments:

VCR reduced to 1 mg if bili > 2

DOX reduced by 25% if bili 2-3, 50% if 3-4, and 75% if > 4.

MTX reduced by 25% if creat 1.5-2.0, by 50% if creat > 2.0

Ara-C reduced to 1 gm/m2 if age >59, if creat > 2.0, or if MTX level at the end of the MTX infusion (0 hours after completion of MTX) was > 19 umol/L

If severe marrow suppression, other adjustments made. See article.

 

Maintenance:

Patients with mature B-cell ALL receive no maintenance.

 

Patients with Ph+ ALL and who can have a transplant, do.

Otherwise, give IFN alpha 5 MU/m2 SQ daily and Ara-C 10 mg SQ daily for 2 years.

 

All other patients:

6-MP 1 gm/m2 IV/1 hour daily x 5

MTX 10 mg/m2 IV/1 hour daily x 5

VCR 2 mg IV

Prednisone 200 mg IV daily x 5

Repeat monthly for 2 years. See article for dose adjustments of maintenance.

 

RELAPSED ALL

 

Cytarabine 3 gm/m2 IV/3 hours daily d 1-5

Idarubicin 40 mg/m2 IVB day 3

IT methotrexate 6 mg/m2 days 2, 4

Neupogen 5 mcg/kg BID starting day 7 until ANC > 5K

 

This led to 38% CR. 3% death due to treatment. Small risk of cardiac toxicity.

 

Ref: A single high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory ALL. Mark Weiss et al, Cancer 95(3):581-587, Aug 2002

 

APL – Maintenance

 

ATRA 45 mg/m2 divided BID for 15 days every three months

6MP 90 mg/m2 qd for two years

MTX 15 mg/m2 per WEEK for two years

 

Start 3-4 wks after achievement of CR.

 

CR rate = 92%

Relapse at 2 yrs = 6% in Atra+Chemo

Role of maintenance:

Relapse at 2 yrs = 8% vs 25% wo maint.

 

European APL Group

Blood 94:1192, 8/99