Rad 1993

REVIEW ARTICLE

Chronic Myelogenous Leukemia: A Concise Update By Hagop M. Kantarjian, Albert Deisseroth, Razelle Kurzrock, Zeev Estrov, and Moshe Talpaz

HRONIC MYELOGENOUS leukemia (CML) is a C clonal myeloproliferative disorder of the primitive he- matopoietic stem cell.’-3 It involves the myeloid, erythroid, megakaryocytic, B-, and sometimes T-lymphoid elements, but not the marrow fibrobla~ts.~,~ CML is characterized by (1) the heterogeneity of the disease among patients, (2) a biphasic or triphasic course, and (3) the presence of a chro- mosomal marker, the Philadelphia chromosome (Ph), in the leukemic Proliferation is a shared feature of CML and other myeloproliferative disorders such as essen- tial thrombocytosis, polycythemia vera, and myeloid meta- plasia/myelofibrosis. Although these entities are usually dis- tinct, overlap in presentation is occasionally observed, resulting in diagnostic confusion. Thus, it is important to confirm the diagnosis of CML by cytogenetic (Ph chromo- some) or molecular studies, because the natural history and treatment of the myeloproliferative disorders are different.

PROGNOSTIC FACTORS AND MODELS IN CML

The disease heterogeneity led to analyses of the prognos- tic factors in CML (Table 1)6-’3 and to the development of prognostic models that categorize patients into good-, inter- mediate-, or poor-risk groups with different survival expec- tations (median survival 2, v 3 to 4, v 5 to 6 years, respec- tively). A synthesis prognostic model, based on these studies, was p ropo~ed’~ (Table 2).

CML PHASES AND DEFINITIONS

CML initially presents in an indolent or chronic phase course, easily controlled with therapy. With conventional treatment, it progresses into an accelerated phase that lasts for less than 1 to 1.5 years, and is followed by a blastic phase resulting in the patient’s death within 3 to 6 months. Twenty percent to 25% of patients die from complications of accelerated phase, while another 20% to 25% develop a blastic phase without the intermediate accelerated phase events. The definition of accelerated phase is vague.15xL6 With more therapies reporting success in accelerated phase, a standardized definition, within which different ap- proaches could be compared, is needed (Table 3).

CURRENT PROGNOSIS IN CML

In the past, the prognosis of patients with CML was poor. The expected median survival was 3 years, and less than 20% of patients were alive 5 years after diagnosis. Prognosis has improved in recent cohorts of CML patients because of (1) earlier diagnosis, (2) improved anti-CML therapy, and (3) better supportive care. With routine screening tests, more patients are detected in the asymptomatic phase of CML, and with lesser degrees of tumor burden (Table 4). In contrast to the previous limited number of effective anti- CML agents (hydroxyurea or busulfan), several additional active drugs and combinations are now available that may improve patient prognosis. These include interferons, low-

dose cytosine arabinoside (ara-C), intensive chemotherapy, and autologous bone marrow transplantation (BMT). Pres- ently, the median survival in CML is about 60 to 65 months. The survival rates are 75% to 85% at 3 years, and 50% to 60% at 5 years (Fig I ) . With a interferon (IFN-a) regimens, 20% to 25% of all patients remain alive with ma- jor durable cytogenetic responses on therapy, as discussed later.

PHILADELPHIA CHROMOSOME, MOLECULAR ABNORMALITIES, AND DISEASE PATHOPHYSIOLOGY

The Ph chromosome initially described a shorter long arm of chromosome 22. It is the result of breaks on chromo- somes 9 and 22, with a reciprocal translocation of the distal genetic material, t(9;22)(q34;ql l).’7,18 This translocation transposes the c-ab1 proto-oncogene from its normal loca- tion, on chromosome 9, to a new position on chromosome 22, in proximity to the breakpoint cluster region (bcr) (Fig 2). A new hybrid BCR-ABL oncogene is formed. It pro- duces an abnormal 8.5-kb RNA that encodes for a 2 IO-Kd (p210) fusion protein. The latter, presumably through its increased tyrosine kinase activity, changes normal hemato- poietic cells into CML cells.”

In Ph-positive CML, the breakpoints within BCR have been assigned to 3’ or 5’ locations. Depending on whether the joinings are between exon 3 or exon 2 of the BCR and exon 2 of ABL, two different RNA messages are formed: b3a2 and b2a2. While the 3’ breakpoints often result in b3a2 and 5’ breakpoints in b2a2 messages, some patients with 5’ breakpoints (zone 3) produce the b3a2 message. These ab- normalities at the DNA and RNA levels have been asso- ciated with different prognostic implications, but the find- ings remain contr~versiaI.’@~~

In Ph-positive acute leukemia, 50% to 80% of patients have a breakpoint proximal to the BCR region, which re- sults in a smaller 7.5-kb RNA and 190-Kd (p190) mes-

These changes have been associated with lymphoid lineage-specific involvement (in contrast to multilineage in- volvement with p2 10 disease), and with shorter periods to acute transformation in animal models. However, except for the development of second chronic phase disease in p2 10 Ph-positive acute leukemia, the clinical features and prognoses are similar in p210 versus p190 acute leuke- mias.26

From the Sections of Leukemia and Biological Studies, the Divi- sion of Medicine, M.D. Anderson Cancer Center, Houston, TX.

Submitted February 5, 1993; accepted April 30, 1993. H.M.K. is a Scholar of the Leukemia Society ofAmerica. Address reprint requests to Hagop M. Kantarjian, MD. M.D. An-

derson Cancer Center, 1515 Holcombe Blvd, Box 61. Houston, T X 77030. 0 I993 by The American Society of Hematology. 0006-49 71/93/8203-0043%3.00/0

Blood, VOI 82, NO 3 (August 1). 1993: pp 691-703 69 1

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692 KANTARJIAN ET AL

Table 1. Poor Prognostic Factors in CML

A. Clinical Older age Symptoms at diagnosis Significant weight loss Hepatomegaly Splenomegaly Poor performance Black race

Anemia Thrombocytosis, thrombocytopenia, megakaryocytopenia Increased blasts, or blasts + promyelocytes in blood or marrow Increased basophils in blood or marrow Collagen or reticulin fibrosis grade 3-4

Longer time to achieve hematologic remission with busulfan

Short remission duration Total dose of busulfan or hydroxyurea therapy required in the first

Lack of significant suppression of Ph-positive metaphases with

Poor initial response to IFN-a therapy

B. Laboratory

C. Treatment-associated

chemotherapy

year to control the disease

intensive chemotherapy or IFN-ol therapy

The mechanisms underlying the growth advantage of CML over normal hematopoietic cells are unknown. The Ph-associated molecular abnormalities reduce the adher- ence of CML cells to the stromal matrix, thus decreasing the time of stroma: hematopoietic cell interaction.*’ This abro- gates the normal maturation of cell surface signals (cytoad- hesion molecules, HLA-DR)28,29 required for the normal proliferation-maturation sequence, allowing CML cells to remain longer in the late progenitor proliferative phase be- fore differentiation. A discordant nuc1ear:cytoplasmic matu- ration in CML may also provide a growth advantage over normal hematopoietic cells.3o331 Although increased prolifer- ation is proposed as the mechanism of CML growth advan- tage, CML cells may live longer than normal cells, and not undergo programmed cell death, or apoptosis, to the same degree. Thus, approaches that induce ( 1) suppression of Ph- positive cells or (2) normalization of their behavior via ad- herence to the stroma, maturation of deficient cell surface signals, differentiation of late progenitor cells, or induction of apoptosis, may be helpful and should be investigated.

RATIONALE FOR INVESTIGATIONAL TREATMENTS IN CML

In the 1970s, intensive chemotherapy was developed, as for acute leukemia, to attempt elimination of the Ph-posi- tive CML clones. The degree of Ph suppression, or cytoge- netic response, was intense but brief. It was also argued that the Ph-positive event was a late phenomenon, and that the Ph-negative cells obtained were still clonal. Thus, suppress- ing Ph-positive cells would not be therapeutically benefi-

This was later refuted by in vitro and in vivo studies showing that the Ph-negative cells were normal, nonclonal hematopoietic stem ~ e l l s . ~ ~ , ~ ~ This strengthened the ratio- nale for attempts to suppress or eliminate the Ph-positive

Table 2. Synthesis Prognostic Staging System for CML ~~

No of Poor-Prognosis

Stage Characteristics Prognostic Determinants

1 0 or 1 Poor-Prognosis Characteristics ~

2 2 1. 2. 3.

Age 2 60 yrs Spleen 210 cm below costal margin Blasts 23% in blood or 23% in marrow

4.

5.

23 3 Basophils 27% in blood or 23% in marrow Platelets 2700 x 1 03/pL

4 Any accelerated Accelerated-Phase Characteristics phase Cytogenetic clonal evolution characteristic Blasts 2 15% in blood

Blasts + promyelocytes 230% in blood Basophils 220% in blood Platelets <loo x i03/pL

CML cells. It was postulated that while the bone marrow of patients with CML is overwhelmed by the growth advantage of the Ph-positive CML cells, a suppressed normal stem cell pool persisted, which could be exploited therapeutically. Treatments that reversed the growth advantage in favor of normal over Ph-positive cells would hopefully change the course of CML, and improve patient prognosis.

Preclinical models have established the causal association between the Ph-associated molecular events and the initia- tion and perpetuation of CML In one such model, c-DNA encoding p2 1 OBCR-ABL was introduced into mouse marrow cells, which were reinfused into lethally irra- diated mice. After 2 to 8 weeks, some of the mice developed CML-like disorders, including ( 1) leukocytosis and spleno- megaly, ( 2 ) monocyte and macrophage extramedullary tu-

Table 3. Definitions of Accelerated and Blastic Phases of CML

A. Blastic phase CML 30% or more blasts in the marrow or peripheral blood Extramedullary disease with localized immature blasts

B. Accelerated phase CML 1. Multivariate analysis-derived criteria

Peripheral blasts 15% or more Peripheral blasts plus promyelocytes 30% or more Peripheral basophils 20% or more Thrombocytopenia <lo0 X 103/pL unrelated to therapy Cytogenetic clonal evolution

2. Other criteria used in common practice Increasing drug dosage requirement Splenomegaly unresponsive to therapy Marrow reticulin or collagen fibrosis Marrow or peripheral blasts 210% Marrow or peripheral basophils IT eosinophils 10% or greater Triad of WBC >50 x 103/pL, hematocrit 125% and

Persistent unexplained fever or bone pains platelets <lo0 x I 03/pL not controlled with therapy

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CHRONIC MYELOGENOUS LEUKEMIA 693

Table 4. Changing Presentation of Patients With Ph-Positive Chronic Phase CML by Year of Referral

Percentage With Characteristic

Before Since 1983 1983

Characteristic Category (N = 336) (N = 494) P Value

Age Ws) Asymptomatic diagnosis Hepatomegaly Splenomegaly Hemoglobin (g/dL) WBC count (X103/pL) Platelet count (1 03/pL) Peripheral blasts Peripheral basophils (%) Marrow blasts (%) Marrow basophils (%) Additional chromosomal

abnormalities other than Ph within 4 wks from diagnosis

260 Yes Yes Yes <12 2100 2700 Yes 27 25 23

Yes

18 15 46 76 58 69 28 65 17 16 40

7

12 37 18 54 48 56 19 56 14 9 35

6

.03 <.01 1.01 <.01 .01 <.01 1.01 .03 NS <.01 NS

NS

Abbreviation: NS. not significant.

mors, and (3) acute lymphoid leukemia.38 These findings, recapitulating the pathogenesis of human CML, ( 1) estab- lish the cause-effect relationship between the BCR-ABL events and CML, (2) suggest that the Ph abnormality is sufficient, not only for development of the chronic phase, but also for disease transformation, and (3) strengthen the notion of improving prognosis in CML, and changing its course, through treatments that suppress or eliminate Ph- positive clones.

THERAPY OF CML

Conventional Therapy Until 1980, hydroxyurea and busulfan were the two most

effective anti-CML agents. They were superior to irradia- tion or other drugs such as melphalan, 6 mercaptopurine, and chlorambucil, provided excellent disease control with minimal toxicity, were inexpensive, and were administered orally. Busulfan provided longer periods of disease control, but was associated with unpredictable prolonged myelosup- pression (10% or less of patients); organ fibrosis (lungs, heart, marrow); and Addison’s-like disease. It is still fre- quently used in countries where socioeconomic consider- ations prevail, and in older patients who are not candidates for BMT, and who do not want frequent follow-ups. Hy- droxyurea has been the drug of choice in patients who are candidates for BMT because of its better toxicity profile. It is used in intermittent schedules to keep the white blood cell (WBC) count between 10 and 50 X 103/pL, or in continuous exposure schedules to control the WBC count at a range of 2 to 5 X 103/pL, ie, a minimal CML tumor burden.

Both agents produce hematologic remissions in 70% to 80% of patients with chronic phase CML. However, these are “pseudoremissions” because cytogenetic studies in treated patients show persistence of Ph-positive cells in the majority (>90%) of marrow metaphases. Ph suppression

has been observed occasionally when unpredictable pro- longed myelosuppression is induced by busulfan therapy. With hydroxyurea therapy, the cytogenetic responses are minor and transient. While these treatments offer effective disease control and survival prolongation, they have not altered the inexorable transformation of CML into the ter- minal phases.

IFN-(U

Therapy with the partially pure human leukocyte IFN, in patients with chronic phase CML, demonstrated a complete hematologic response (CHR) rate of 70%, and a cytogenetic response rate of 40%.40 This was followed by several trials with the recombinant (Y interferons (IFN-a) alone:’ or in combinations with other biologic agents (IFN-.I, DFMO), with initial or later cyclic intensive chemotherapy, hydroxy- urea, and low-dose ara-C. These studies have confirmed that CHRs are achieved in 70% to 80% of patients, cytoge- netic responses in 40% to 60%, and major cytogenetic re- sponses (Ph suppression to <35%) in 30% to 40% (Table 5). Cytogenetic responses were categorized as complete if Ph- positive cells were 0%, partial if they were 1 % to 34%, and minor if they were 35% to 90%. The median survival of patients treated with IFN-a regimens in early chronic phase CML is shown in Fig 1.

Results of IFN-(Y therapy in CML have now been re- ported by several investigator^^^-^^ (Table 6). Differences in CHR and cytogenetic response rates in various trials may be related to (1) the CML phase in which patients are treated, (2) the patient risk group and pretreatment characteristics, and (3) the dose-schedule of IFN-a (Table 7). Alimena et al” randomized patients to receive IFN-a 2 X lo6 U/m2 three times weekly, or 5 X lo6 U/m2 three times weekly. Among 33 patients treated at the lower dose schedule, 8 (24%) achieved CHR, compared with 14 of 30 patients (47%) treated at the higher dose schedule ( P = .06). Among 21 patients who failed to achieve a response at the lower dose schedule and who were treated at the higher dose sched- ule, 8 (38%) achieved CHR. On the daily dose schedule that they used subsequently, 7 of the first 8 patients treated

100

80

(N = 313) \ I

*O t 0 24 40 72 96 120

Survlval from Start of Therapy (Months)

Fig 1. Survival of patients with Ph-positive CML treated with IFN-a-based regimens in early chronic phase.

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694 KANTARJIAN ET AL

Chromosome 9

n

3 Chromosome 22 t(9;22) (q34;qll)

U

Chromosome 22 Chromosome 9

BCRABL hybrid oncogene

8.5 Kb mRNA (b3a2 message) + I

1 210 KD protein

achieved CHR (87%). In early chronic phase CML, IM-a at 5 X lo6 U/m2 daily, or at the lower maximally tolerated individual dose, is associated with better hematologic and cytogenetic response rates. Side effects. IM-a is associated with early flulike side

effects (fever, chills, postnasal drip, anorexia, lack of appe- tite) in most patients, which ( I ) are not dose-limiting, (2) can be managed symptomatically (bedtimedose, acetamino- phen), and (3) are minimized by starting IM-a at 50% of the dose for the first week. Reducing the initial WBC counts to 10 to 20 X 103/pL with chemotherapy also reduces the

Table 5. Results of IFN-U Studies in CML at MDACC

Study-Year (reference)

Human IFN-a-1982 (40) Recombinant IFN-a-1984 (41)

IFN-a f cyclic intensive chemotherapy-1 986

IFN-a + hydrea-1988 IFN-a + low-dose ara-C-1989

IFN-a + IFN-7-1985

NO. Patients

51 35 36

68 79 44

Percent

Cytogenetic Response

cnR 71 80 68

82 86 70

Any Major

41 18 54 40 47 31

66 43 62 41 55 32

Total 313 77 56 35

Fig 2. The Ph chromosome in CML and associated molecu- lar abnormalities.

leukocytosis-associated side effects (fever, chills, musculo- skeletal pains). Tachyphylaxis develops within 1 to 2 weeks. Late side effects are dose-limiting in 10% to 25% of patients, and include persistent fatigue; weight loss; neurotoxicity (depression); a triad of depression, fatigue, and insomnia (manageable with small doses of antidepressants at bed- time); and occasional immune-mediated complicati~ns?~.~~ These have included immune-mediated hemolysis or thom- bocytopenia, collagen vascular disorders such as rheuma- toid arthritis and systemic lypus erythematosis, and im- mune-mediated nephrotic syndrome and hypothyroidism. Rare cases of cardiac dysfunction (arrythmias, congestive heart failure) have been reported and may be immune-me- diated. These necessitate immediate discontinuation of IFN-a, standard treatment for heart failure, and steroid ther-

Table 6. Results of IFN-a Studies in CML

No. (%) No.

Study (reference) Patients cnR Ph Suppression

M.D. Anderson Cancer Center 313 240 (77) 175 (56)

Alimena et al(42) 63 29 (46) 27 (43) Niederle et a1 (43) 41 23 (56) 14 (34) Ozer et al(44) 107 63 (59) 3 1 /80 (44) Freund et a1 (45) 27 10 (37) 5 (19) Montastruc et a1 (46) 38 32 (84) 24 (63)

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CHRONIC MYELOGENOUS LEUKEMIA 695

Table 7. Parameters Associated With Differences in Resoonse to IFN-a in Ph-Positive C M L

Parameter

Percent

Cytogenetic Response

Category CHR Any Major

CML phase (IFN-a 5 x 10' Early chronic U/m2 daily) Late chronic

Accelerated Blastic

Risk category in early Low chronic phase Intermediate

High 5 X 10' U/m2 daily 5 x 10' U/m2 Tiw 2 x 10' U/m2 Tiw c2 X 10' U/m2 Tiw

Dose of IFN-a

Abbreviation: Tiw, 3 times weekly.

60-80 50-60 30-40 20-30 80-90 50-60 20-60 80 70

30-40 20-30

40-50 10-20 cl0 <10 60 40

10-20 50-60 40 20

c10

20-30 <10

0 0 40

20-30 5-10 40 20

5-10 0 -

apy if indicated. Immune-mediated hypothyroidism does not require IFN-a discontinuation and is managed by re- placement therapy.

Dose reductions are required for (1) grade 3 or 4 toxicity (hold therapy until recovery then start at 50%), (2) persistent grade 2 toxicity not improved with symptomatic support (25% dose reduction), or (3) if the WBC count decreases to below 2 X 103/pL or platelets below 60 X 103/pL (25% dose reductions). Elderly patients (age 60 years or older) tolerate therapy less well than younger patients.

To evalu- ate the long-term course of patients, and allow for matura- tion and follow-up of cytogenetic responses, patients treated until 1988 were reviewed. Cytogenetic studies were per- formed every 3 months in the first 2 years, then every 4 to 6 months. The duration of cytogenetic response is calculated from the time of the achievement of any cytogenetic re- sponse (Fig 3, A and B), or from the time of achievement of the best cytogenetic response (Fig 3, C), until recurrence of more than 90% Ph-positive cells. Durable cytogenetic re- sponses were noted in about 30% of patients (Table 8, Fig 3).

Of the 49 patients achieving cytogenetic complete remis- sion (CR), 45 (92%) have durable cytogenetic responses for periods ranging between 2 and 8 years, whereas 4 have lost their cytogenetic response (ie, reverted back to 90% or more Ph-positive metaphases) (Table 8). Thirty-four of the 49 pa- tients were in a continuous cytogenetic CR (ie, Ph status 0%) with repeated studies. Sixteen of the 34 patients were taken off IFN-a because of toxicities (5 patients) or patient or physician choice (1 1 patients; continuous cytogenetic CR for more than 2 years): 7 of the 16 continue in cytogenetic CR for 12+ to 56+ months (median 34 months); 6 had Ph recurrence but went back to 0% Ph-positivity (3 patients) or less than 35% Ph-positive (3 patients) with reinstitution of IFN-a; and 3 had recurrence of Ph-positive metaphases but are on observation off IFN-a therapy (cytogenetic but not hematologic relapse). Among the remaining 11 patients, 6 fluctuate with Ph-positive metaphases of 0% to lo%, whereas 5 have more than 10% Ph-positive metaphases, but are in continuous cytogenetic response on IFN-a therapy (2 with less than 35% Ph-positive metaphases). Thus, currently

Long-term follow-up of cytogenetic responses.

28 (18 + 7 + 3) of the 49 patients (57%) are in continuous cytogenetic CR on or off IFN-a therapy; while 39 patients (28 cytogenetic CR, 1 1 cytogenetic PR) (80% of total) are in a durable major cytogenetic response.

Associations of cytogenetic responses with prognosis. Ac- counting for the time to achieve the best cytogenetic re- sponse (median time 22 months for complete, 18 months for partial, 12 months for minor cytogenetic responses, re- spectively), the duration of cytogenetic response was longest in patients achieving a complete cytogenetic response (Fig 3). This is not surprising because, in most other tumors, the lowest detectable tumor burden achieved (ie, CR) is the only response that is associated with durable remissions and with prolongation of survival or disease-free survival. Once such a low tumor burden is obtained in a substantial fraction of patients (40% to 60%), significant survival prolongation may be observed for the total population under treatment. A similar significant association between the cytogenetic re- sponse at 12 months and survival was also reported by the Italian Cooperative Study Group in CML.4' Using a land- mark analysis, Ozer et alM did not find a significant correla- tion between cytogenetic response and remission duration or survival. However, their analysis combined cytogenetic CR and PR as one category (which might have diluted the association), and only 14 patients were in cytogenetic CR.44

Zuffa et aIs1 updated their comparative study that ran- domized patients to IFN-a at 5 X lo6 U/m2 daily (218 pa- tients) or hydroxyurea (104 patients). The long-term follow- up showed major cytogenetic response at 4 years in 25% of patients receiving IFN-a and in 0% of those treated with hydroxyurea. The median survivals were significantly better in IFN-a-treated patients overall (not reached v 49 months, P = .004), and within low-intermediate (not reached v 50 months, P = .04), and high-risk groups (56 v 38 months, P =

Investigating the long-term prognosis of patients, Lazzar- ino et a15' analyzed IFN-a as a treatment variable for prog- nosis, showing it to be significantly favorable in good- and intermediate-risk patients, but not in those with poor-risk disease.

Interpretation of the maturing experience. While the re- sults of Zuffa" and Lazzarino et a15' support association between IFN-a and improved survival, the fact that only 25% of patients have complete responses suggests that the beneficial effect on survival in the total denonimator may not be reproducible in other studies. In general, to observe the effect in the whole population, at least 40% of patients should achieve a minimal tumor burden (ie, CR for solid tumors, cytogenetic CR for CML) if that response is asso- ciated with at least a 25% improvement in progn6,:is (10% overall improvement; P = .05; power 80%; 100 patients in study and control groups).

These findings have important therapeutic implications. If the positive effect of IFN-a on survival of the total popula- tion is shown in other studies, the treatment recommenda- tions might change to advise continuing IFN-a therapy in all patients with CML, regardless of the cytogenetic re- sponse, aiming for the survival benefit. However, if the sur- vival association is not solidly confirmed, then only patients

.02).5*

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696

A 100

2 80 E 0

5 % ’5 60 c .o,

E & 40

L

g z

0” 0 L

20

0

G 7 (n = 101)

KANTARJIAN ET AL

Fig 3. Duration of cytogenetic response (A) overall; and by cytogenetic response from (E) start of therapy, and (C) from time of achievina the best

Duration of Cytogenetic Response (Months)

“

120 response in patients treated from 1982 to 1988 (M.D. Anderson data base in CML). RefertoTable8

0 24 48 72 96

and text for discussion.

Cytogenetic CR (n = 49)

‘i. \ Cytogenetlc PA (n = 14) : L -----_--------. .. . .. ... . . . . . . , . Cytogenetlc Minor (n = 38) .........................

0 24 48 72 96 120

Duratlon of Cytogenetic Response (Months)

who achieve a major cytogenetic response would continue on IFN-a therapy (discussed later under “Proposed Se- quence of Treatments in CML”). Future studies with IFN-a combinations would then aim to achieve complete cytoge- netic response rates of 40% or more before other random- ized clinical trials are planned.

In summary, the maturing experience with IFN-a regi- mens (1 ) shows median survivals of 60 to 65 months with

Table 8. Long-Term Follow-up d Responses in Patients Treated With IFN-a-Based Regimens (1982-1 988)

Parameter No. (%)

Total treated Complete hematologic response

Cytogenetic response

Complete Partial Minor

Overall

190 (100) 141 (74)

No. (%) No. Durable [%I

49 (26) 45 [92]

38 (20) 6 [IS] 14 (7) 5 [361

101 (53) 56 [29% of total; 55% of cytogenetic resoondersl

c 100

80 :: 5 : :

E 2 e:,

0”

0

S,U 60

a -

2 g, 40 0 -

20

0

.I

:L : I . I *. I . I : I :I

?I

*a--

:.. I .. I

i,CI ’: Cytogenetic PR (n = 14) . L--------

\. cytogenetic Minor (n = 38) .............................. 0 24 48 72 96 120

Duration of Cytogenetlc Response (Months)

25% of patients being in durable cytogenetic remissions, and ( 2 ) suggests the superiority of IFN-ar over conventional therapy, as measured by cytogenetic response and survival.

Other IFNs The promising results with IFN-a encouraged the search

for other IFNs or biologic agents with potential anti-CML activity. IFN-y differs from a and j3 IFNs in its biologic properties, mechanisms of action, and cell surface recep- tors. Studies investigating y-IFN in CML have shown defi- nite but modest activity, with a CHR rate range of 20% to 30%.53 Combining IFN-a with y-IFN in ( I ) a simultaneous dose schedule using the full dose of IFN-a and a low (in vitro synergistic) dose of IFN-7, or ( 2 ) in a sequential fash- ion using alternate-day or alternate-week schedules of the two IFNs, has produced disappointing result^.^^^^' IFN-j3 has had limited investigation in CML with negative re- s u l t ~ . ~ ~ Studies with the “concensus” IFN, a synthetized molecule that presumably incorporates the active moieties of different subspecies of ar IFWs, are underway.

Combinations of IFN-a and Other Agents To improve the prognosis beyond that obtained with

IFN-a alone, investigations have combined it with other

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CHRONIC MYELOGENOUS LEUKEMIA 697

Table 9. Therapy With IFN-a Alone or With Low-Dose ara-C in Late Chronic-Phase CML

No. (%)

No. Cytogentic 3-yr CML Phase Therapy Patients CHR Response Survival (%I

Late chronic IFN-a + ara-C 40 22 (55) 6 (1 5) 75 IFN-a 39 11 (28) 2 (5) 48

P = . 0 2 P = .15 P<.O1 Accelerated (clonal IFN-a + ara-C 16 8 (50) 4 (25) 74

evolution only) IFN-a 9 6 (66) 2 (22) 49

effective anti-CML agents including busulfan, hydroxyurea, initial or cyclic intensive chemotherapy, and low-dose ara- C. Combining busulfan with IFN-a proved to be difficult because of the cumulative effect on prolonged myelosup- pression. Adding intensive chemotherapy to IFN-a was not associated with better results than with IF"-(U alone, per- haps because of the short-term exposure of CML cells to the effect of chemotherapy (only 3 initial courses, or once every 6 months) mandated by the serious myelosuppressive side effects.57

The combination of IF"-a and hydroxyurea is attractive in clinical practice because of its ease of administration. This regimen provides (1) rapid disease control, ( 2 ) a better CHR rate, (3) a lower incidence of side effects attributed to leukocytosis (fever, chills, musculoskeletal syndrome), and (4) a longer duration of disease control. However, it is not associated with improved cytogenetic response rates (over- all, major, durable).

Ara-C was combined with IFN-a because of its selective anti-CML effect in vitro, and its capacity to induce cytoge- netic remissions in treated patient^.^^,^^ With low-dose ara- C therapy in chronic phase CML, Sokal and Bigner" and Cannistra et a159 observed cumulatively Ph suppression down to a median of 27% Ph-positive metaphases (range 0% to 84%) in 6 of 8 patients. Low-dose ara-C is associated with less myelosuppressive side effects than intensive chemother- apy, and provides longer exposure of CML cells to the treat- ment (about 1 week every month) and, hence, potentially better suppression of CML clonal evolution. In late chronic- phase CML, the combination of IFN-a and low-dose ara-C was associated with significantly higher CHR rates com- pared with IFN-a alone, a trend for better cytogenetic re- sponse rates, and with significantly longer survivalm (Table 9). It also induced suppression of clonal evolution in 5 of 20 patients (25%) treated in accelerated phase (16 patients with clonal evolution only, see Table 11; 4 patients with other accelerated phase features with or without clonal evolu- tion).

In a randomized study, Guilhot et a16' treated patients with early chronic-phase CML with IFN-a plus low-dose ara-C (39 patients) or with IFN-a alone (36 patients). Both groups had received hydroxyurea during remission induc- tion to achieve rapid cytoreduction until CHR was ob- tained. Compared with IFN-or therapy alone, the combina- tion of IFN-(U plus low-dose ara-C was associated with a higher complete cytogenetic response rate (8% v 28%; P < .01) and with nonsignificant trends for a higher major cyto-

genetic response rate (30% v 44%), and for disease control at 12 months (60% v 80%).

Allogeneic BMT Allogeneic BMT is curative in CML, with significantly

better disease-free survival rates in chronic, compared with accelerated or blastic phases (Table 10). Candidate patients should be offered matched or one antigen-mismatched re- lated allogeneic BMT in chronic phase, before disease trans- formation.

The timing of allogeneic BMT in chronic phase is more controversial because of the risks of the procedure. In chronic phase CML, better results are achieved (1) in younger patients, (lower risk of early and graft-versus-host disease [GVHDI-associated mortality), (2) when BMT is performed in early chronic phase, and (3) in patients not exposed to busulfan A lower incidence of BMT morbidity and mortality from GVHD has been observed with T-cell-depleted BMT, which was counterbalanced by the higher incidence of graft failure and leukemia re-

The lower disease-free survival rates with transplantation later in chronic phase CML are not due to a higher inci- dence of leukemia relapse (ie, more resistant clones from longer disease duration), but to a higher BMT mortality. This suggests that host- (age, organ function) or treatment- related factors (prior busulfan exposure) are partly responsi- ble for this difference. This difference in survival rates, while statistically significant in the international BMT registry (IBMTR) in over 1,000 patients evaluated, is in the range of 5% to 1096, and may not be relevant to individual patients,68 particularly when accounting for age and prior therapy con- siderations. In a subset analysis of patients receiving non-T- cell-depleted allogeneic BMT, Goldman et a169 reported both the duration of chronic phase, and exposure to busul- fan therapy, to be independent prognostic factors for patient outcome. The European BMT Registry (EBMTR) has not shown a survival difference by time to BMT, but patients

iapse.66,67

Table 10. Results of Allogeneic BMT in CML

Percent

CML Phase Disease-free Leukemia

Survival Relapse

A. Results by CML Phase Chronic 40-60 5-30 Accelerated 15-25 50-60 Blastic 15 or less 60-80

% With Parameter by Age of Patients (yrs)

Parameter t 2 0 20-29 230

B. Results by Age in Chronic- Phase CML

Early mortality 5-10 10-20 10-25 Late mortality 5-10 10-20 10-25 Leukemia relapse 20 20 20

Disease-free survival 60-70 40-50 40

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698 KANTARJIAN ET AL

with worse expected prognosis may have received trans- plants earlier in chronic-phase CML.70 The long-term fol- low-up studies from both registries show disease-free sur- vival rates of 38% at 5 years, a figure lower than projections from earlier reports, with a continuous pattern of late re- lapses (relapse rates 10% at 2 years, 25% at 5 years). This late relapse pattern, not seen in acute leukemia, may be caused by the more primitive stem cell involvement in CML. Both of these updates have included patients who had undergone T-cell-depleted allogeneic BMT, and the disease-free sur- vival rates in non-T-cell-depleted BMT are higher. In the EBMTR studies, patients with prior IFN exposure and those who underwent splenectomy before BMT did not have different outcomes compared with those who had

Allogeneic BMT with matched unrelated donors (MUD) has yielded encouraging r e s ~ l t s . ~ ~ , ~ ' The median time from the start of the search to BMT was 8.4 months. The proce- dure was associated with ( 1 ) a higher incidence of graft fail- ure (16%), and ( 2 ) higher incidences of grade I11 and IV acute GVHD (54%) and of extensive chronic GVHD (52%). Overall, the 2-year disease-free survival rate was 3 1%, and ranged from 14% to 43% depending on the patient age and degree of HLA-mat~hing.~' Thus, while promising, MUD allogeneic BMT is presently associated with significant mor- bidity and mortality, particularly in older patients. It is indi- cated in patients with a poor prognosis (acute leukemia in 2 first relapse, CML transformation). Its benefit versus risk should be carefully weighed in chronic-phase CML, particu- larly among older patients, in relation to other investiga- tional modalities, and to the natural course of the disease with current treatments.

Proposed Sequence of Treatments in CML All patients with CML transformed (accelerated, blastic)

phases and those with a syngeneic donor should be offered allogeneic BMT ifthey are candidates for the procedure (age less than 50 to 55 years, available matched or one antigen mismatched related donor).

Younger patients (age cut-off defined by investigators ac- cording to their experience in different age subgroups) would be offered related allogeneic BMT in early chronic phase when possible, because of the high disease-free sur- vival rates and low morbidity and mortality in these age groups.

For the remaining patients, an initial trial of IFN-a- containing regimen may be indicated. If patients achieve a significant response (any cytogenetic response at 6 months, Ph-positive cells less than 50% to 65% at 12 months) they will continue on therapy unless the response is lost. The others will be offered allogeneic BMT from related donors, or investigational treatments such as MUD allogeneic BMT, autologous BMT, or new agents (homohamngton- ine, others) or combinations (Fig 4).

Patients who achieve a complete durable cytogenetic re- sponse documented over a 6-month period should have an autologous marrow storage. In them, IFN-a therapy should be held for at least 1 month before autologous marrow pres- ervation for ease of procedure and storage of an adequate

Early chronic phase CML if n z available

Cytogenetic response * * Any Ph < at 50% 6 months at 12 months

If not

Investigational approaches

HUD allogeneic BMT I : Autologous BHT 1 . New agents or regimens

Fig 4. Proposed treatment approach in patients with CML.

marrow for BMT (3 X 10' nucleated cells or more/kg, IO4 or more GMCFC/kg).

IFN-a therapy was thought not to benefit patients in late chronic-phase CML. Recent studies showing a survival ad- vantage of IFN-a versus h ~ d r e a ~ ' . ~ ' and of IFN-a plus low- dose ara-C in late chronic phase CMLm suggest otherwise. Patients in late chronic-phase CML who are not candidates for allogeneic BMT (related, MUD), should consider an in- vestigational trial before deciding on maintenance with IFN-a therapy (IFN-a plus low-dose ara-C or hydroxyurea) for optimal benefit (Fig 4).

Autologous BMT Autologous BMT in CML transformed phases was asso-

ciated with a high rate of reestablishment of a short-lasting second chronic phase. In chronic-phase CML, autologous BMT with infusions of predominantly Ph-positive autolo- gous stem cells (peripheral, marrow) produced transient cy- togenetic remission^.^^,^^ Follow-up studies have suggested a longer survival with autologous BMT. However, similar to autologous BMT studies in other tumors (acute leukemia in first CR, multiple myeloma, breast and lung cancers), it is difficult to dissociate the effect of patient selection, and lead time bias, from that of BMT. Comparative studies with pa- tients treated with other modalities and matched for age, organ function, and time to BMT may help clarify the issue.

Autologous stem cell transplant using in vivo (chemother- apy, IFN) or in vitro purging (chemotherapy, IFNs, long- term liquid cultures, positive selection for CD34-positive normal stem cells, negative selection for CML is an exciting strategy. The purpose is to infuse stem cells max- imally enriched with normal hematopoietic cells and de- pleted of Ph-positive clones.

Using long-term liquid (Dexter) cultures for in vitro purg- ing of CML marrows, Barnett et a174 screened 88 patients and identified 33 (38%) to be suitable for the large-scale purging procedure. Twenty of the 33 patients underwent purged autologous BMT (14 in first chronic phase; 6 in later

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CHRONIC MYELOGENOUS LEUKEMIA 699

phases). Graft failure was noted in 5 patients (20%). Of 14 evaluable patients by cytogenetic studies, 12 (86%; 60% of total) achieved a cytogenetic CR, and the other 2 had a cytogenetic PR. After a median follow-up of 15 months (range 6 to 51 months), Ph-positive recurrence was ob- served in 8 of the 12 patients, and 6 received IFN-a therapy. Five patients (20% of total) are currently disease free for 14, 28,29,32, and 5 1 months, the latter 2 with IFN-a therapy.74

Alimena75 summarized the Italian experience in patients with CML who underwent autologous BMT intensification if they had not achieved a desirable cytogenetic response with IFN-a therapy. Fifteen patients, whose median percent of Ph-positive cells was 72% after a median duration of 20 months of IFN-a therapy, had marrow harvest and under- went autologous BMT: 5 remain in cytogenetic remission (Ph-positive less than 35% in 2, and more than 35% in 3).75 In that same analysis, of a total of 48 patients undergoing autologous BMT before (26 patients) or after IFN-a therapy (22 patients), 11 (23%) achieved favorable cytogenetic re- s p o n s e ~ . ~ ~

These relatively mature studies, as well as others using different forms of in vitro purging (IFN-7, CD34-positive stem cell selection, negative selection of Ph-positive cells), or in vivo purging (intensive chemotherapy), encourage fur- ther investigations of purged autologous BMT programs as an intensification procedure to (1) to increase the rate of durable cytogenetic responses and ( 2 ) to prolong survival.

The potential use of oncogene-targeted approaches (anti- sense oligonucleotides, conjugated toxins) for in vitro purg- ing or in vivo therapy in autologous BMT are of interest. Combinations of these approaches may result in selective relatively nontoxic anti-CML therapies.

Other Investigational Modalities New agents such as homoharringtonine have shown

promising anti-CML ef f i~acy .~ ' ,~~ Homoharringtonine, used in a low-dose prolonged-infusion schedule in patients with late chronic-phase CML, resulted in CHR in 68% of patients, and in cytogenetic responses in 3 1 % ( 1 7% ma- jor)." Its activity in combination with IFN-a in early chronic-phase CML is under in~es t iga t ion .~~ Other ap- proaches of interest include differentiating agents (reti- noids), agents that block cytokines that may mediate CML progression (interleukin- 1 [IL- 13 receptor antagonists; I L 1 soluble receptors),80 and new chemotherapeutic drugs.

QUESTIONS OF INTEREST IN THE MANAGEMENT OF CML

Ph Chromosome-Negative CML About 10% of patients with a morphologic picture of

CML do not have the Ph chromosome by cytogenetic analy- sis. One third of them will have BCR rearrangement by Southern blot molecular analysis (Ph-negative BCR-posi- tive CML) and have a similar clinical picture, response to therapy, and outcome as Ph-positive CML.'' The remain- ing patients have a spectrum of disorders including myelo- dysplastic syndrome with a myeloproliferative component, chronic myelomonocytic leukemia, and true "Ph-negative, BCR-negative CML." The latter, unlike Ph-positive CML,

may have a low propensity for blastic transformation (25% to 50%), and an intermediate prognosis between chronic myelomonocytic leukemia (CMML) and Ph-positive CML.

Thrombocytosis in CML Thrombocytosis in CML is a poor prognostic feature, and

may be associated with thromboembolic or bleeding com- plications. In most patients, thrombocytosis responds to the regimen used in controlling CML. IFN-a is effective in con- trolling thrombocytosis in more than three quarters of pa- tientsS2 Anagrelide, an agent that prevents megakaryocytic maturation, also reduces the platelet counts, but has no ef- fect on marrow megakaryocytosi~.~~ In patients refractory or intolerant to the above treatments, thiotepa is effective at doses of 75 mg/m2 intravenously every 2 to 3 weeks until response occurs.

CML and Pregnancy Pregnant women with CML may be managed with re-

peated leukophereses during the first one or two trimesters of pregnan~y.'~ Leukopheresis may be performed when the WBC count exceeds 70 to 100 X 103/pL, or in symptomatic conditions. Hydroxyurea has been used in the later stages of pregnancy without untoward or teratogenetic effects on the fetus. IFN-a is teratogenic in animal models. Two of our patients became pregnant while undergoing IFN-a therapy; the treatment was discontinued, and both delivered normal babies. However, patients on IFN-a therapy should have adequate contraception, because the treatment has the po- tential of inducing serious complications in the newborn (underweight babies, malformations).

Role of Splenectomy in CML The spleen may be an initial site of CML transformation

in a minority of patients (? less than These may be the patients with persistent significant splenomegaly despite adequate disease control in the BM and blood. Studies ran- domizing patients to splenectomy or no splenectomy in early chronic phase,86 or before allogeneic BMT have not shown a survival ad~antage. '~,~' Splenectomy before alloge- neic BMT may result in earlier hematopoietic recovery, but is associated with a higher incidence of GVHD in patients without palpable splenomegaly. Based on current knowl- edge, splenectomy in chronic-phase CML may be consid- ered for persistent significant splenomegaly on optimal ther- apy, particularly with evidence of hypersplenism, or with suboptimal treatment delivery because of anemia or throm- bocytopenia. Splenectomy in CML transformation may be associated with increased morbidity and mortality without an obvious therapeutic benefit.

When Should Molecular Studies Be Performed in CML? In patients with a morphologic picture of CML but no

Ph-positive metaphases, Southern blot analysis for BCR re- arrangement will identify the subset of Ph-negative, BCR- positive CML patients. This will help directing their therapy (as for Ph-positive CML) and prognosticating on the course of the disease.

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700 KANTARJIAN ET AL

The value of molecular studies to detect 3’ versus 5’break- points, or b3a2 versus b2a2 messages, is controversial. It should be pursued in investigational studies, but not as rou- tine tests in clinical practice.

In the follow-up of patients on treatment, BCR rearrange- ment quantification has not yet been standardized in rela- tion to cytogenetic studies. Once the equivalence of the two studies for measuring the degree of Ph-suppression is estab- lished, serial follow-ups with BCR quantification may be easier, faster, and less expensive. The test is currently useful to monitor the effect of therapy in patients with Ph-negative BCR-positive disease. Southern blot analysis is equivalent, but not superior, to cytogenetic studies in assessing minimal residual disease (ie, Ph-positive 0%).

Polymerase chain reaction (PCR) studies to detect resid- ual disease at to level is an important investiga- tional tool in Ph-positive CML. In our experience, PCR studies for BCR-ABL were positive in all 40 patients who had 0% Ph-positive metaphases by cytogenetic studies after IF%-a therapy.” Other groups have reported some cases with P C R - n e g a t i ~ i t y . ~ ~ ~ Detection of residual disease at this level may not be clinically relevant because it has not predicted consistently for subsequent relapse. Among pa- tients studied after allogeneic BMT, more than 75% will have at least one PCR-positive test within 12 months post BMT, and 40% to 53% will be positive at 12 month^.^^-^* Only 25% of the latter group will have CML relapse. Conse- quently, PCR studies for BCR-ABL should be pursued in investigational studies of therapeutic interventions in CML, but not in current community practice.

FUTURE DIRECTIONS

Future investigations should aim at improving and maxi- mizing the intensity and duration of cytogenetic responses in CML, ie, suppressing the Ph-positive clones responsible for disease propagation and progression. This could be achieved through (1) optimizing IFN-a combination regi- mens (with low-dose ara-C, homohamngtonine, or other agents); (2) investigating new approaches in allogeneic BMT that improve the efficacy and safety of the procedure; (3) pursuing the leads in purged autologous BMT as an intensi- fication procedure, followed by IFN-a or other mainte- nance therapies; (4) developing selective antioncogene tar- geted therapies; and (5) discovering new agents with specific anti-CML efficacy. The sum of such programs will hope- fully improve significantly the prognosis in CML over the next decade.

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1993 82: 691-703  

HM Kantarjian, A Deisseroth, R Kurzrock, Z Estrov and M Talpaz Chronic myelogenous leukemia: a concise update 

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