3.1.

CML
3.1.1. Definition
CML is a malignant clonal disorder of hematopoietic stem cells that results in increases in not
only myeloid cells but also erythroid cells and platelets in peripheral blood and marked
myeloid hyperplasia in the bone marrow.
3.1.2. Etiology
he diagnosis of CML is usually based on detection of the !hiladelphia "!h#
chromosome. his abnormality$ first described as a shortened chromosome 22 in 1%&' and
then as a t"%(22# translocation in 1%)3$ is present in %* percent of patients. +nother * percent
ha,e comple- or ,ariant translocations in,ol,ing additional chromosomes that ha,e the same
end result$ which is fusion of the
BCR "breakpoint cluster region# gene on chromosome 22 to the ABL "+bleson leukemia
,irus# gene on chromosome %. he !h chromosome is found in cells from the myeloid$
erythroid$ megakaryocytic$ and . lymphoid lineages$ indicating that CML is a stem/cell
disease.
3.1.3. Epidemiology
CML occurs in all age groups$ but most commonly in the middle/aged and elderly. 0ts annual
incidence is 112 per 1''$''' people$ and slightly more men than women are affected. CML
represents about 1*12'2 of all cases of adult leukemia in 3estern populations.
415
he only
well/described risk factor for CML is e-posure to ioni6ing radiation( for e-ample$ increased
rates of CML were seen in people e-posed to the atomic bombings of 7iroshima and
8agasaki
425
.
Leukemia is also rarely associated with pregnancy$ affecting only about 1 in 1'$''' pregnant
women.
3.1.9. !athogenesis and !athophysiology
During the e,olution to a blast crisis$ a range of nonrandom$ secondary chromosomal
changes occur$ including duplication of the !h chromosome and trisomy :. Mutations or
deletions of tumor/suppressor genes such as p16 and p53 occur with ,ariable fre;uency and
presumably contribute to the malignant phenotype. he molecular conse;uence of the t"%(22#
translocation is the creation of the fusion protein .C<1 +.L$ which is a constituti,ely acti,e
cytoplasmic tyrosine kinase. Depending on the site of the breakpoint in the BCR gene$ the
fusion protein can ,ary in si6e from 1:* kd to 23' kd. Each fusion gene encodes the same
portion of the +.L tyrosine kinase but differs in the length of .C< se;uence retained at the
8 terminal. 8early all patients with typical chronic/phase CML e-press a 21'/kd .C<1 +.L
protein$ whereas patients with !h/positi,e acute lymphoblastic leukemia e-press either a 21'/
kd or a 1%'/kd .C<1+.L protein "the latter is sometimes referred to as 1:*=1%' kd#.
<ecently$ a larger$ 23'/ kd .C<1+.L fusion protein was found in a subgroup of patients
with CML who presented with a lower white/cell count than is usual for the disease and in
whom progression to blast crisis was slow.
he fact that fusion proteins of different si6es can be correlated with different outcomes
has led to laboratory studies of the biologic acti,ity of the proteins. he results indicate that
the 1%'/kd .C<1+.L protein has greater acti,ity as a tyrosine kinase and is a more potent
oncogene than the 21'/kd protein$ suggesting that the magnitude of the tyrosine kinase signal
affects the e-pression of the disease. he cloning of the !h translocation has led to the
de,elopment of highly sensiti,e and specific molecular probes that are ,aluable tools for
monitoring responses to therapy. >uantitati,e cytogenetic information can be obtained by
fluorescence in situ hybridi6ation without the need to culture cells or analy6e cells in
metaphase.
!olymerase/chain/reaction "!C<# testing of peripheral/blood <8+ is highly sensiti,e?
it can detect 1 !h/positi,e cell e-pressing the .C<1+.L fusion transcript in 1' to 1' normal
cells. @ne conse;uence of these newer diagnostic tests has been the reclassification of the
response to treatment on the basis of hematologic$ cytogenetic$ and molecular remissions. +
hematologic remission indicates a return of peripheral/blood cell counts and bone marrow
morphology to normal$ whereas cytogenetic and molecular remissions indicate the
disappearance of the !h chromosome or the BCR ABL gene$ respecti,ely. he fa,orable
prognostic ,alue of hematologic and cytogenetic remissions is clear$ on the basis of data on
sur,i,al among patients treated with interferon alfa$ but the clinical ,alue of molecular testing
remains to be defined. 8egati,e !C< results in patients treated by allogeneic bone marrow
transplantation clearly predict a fa,orable outcome$ but positi,e results are difficult to
interpret$ because of the e-treme sensiti,ity of the !C< assay. Aor e-ample$ the results of
!C< assays can remain positi,e in interferon/treated patients who are in complete
cytogenetic remission and patients who ha,e sur,i,ed for se,eral years after bone marrow
transplantation$ two subgroups with ,ery fa,orable outcomes$ presumably because small
numbers of leukemic cells remain. 8ewly de,eloped ;uantitati,e !C< assays allow
monitoring of the le,el of .C<1 +.L messenger <8+ transcripts o,er time. @n the basis of
these assays$ a progressi,e increase in minimal residual disease after allogeneic
transplantation appears to predict e,entual relapse.
3.1.*. Clinical Manifestation and Diagnosis
he median age at presentation is *3 years$ but all age groups$ including children$ are
affected. Most patients also ha,e thrombocytosis$ which is consistent with the presence of a
defect in a pluripotent hematopoietic stem cell. he typical symptoms at presentation are
fatigue$ anore-ia$ and weight loss$ but about 9' percent of patients are asymptomatic$ and in
these patients$ the diagnosis is based solely on an abnormal blood count "able 1#. he most
common abnormality on physical e-amination is splenomegaly$ which is present in up to half
of patients. he natural history of CML is progression from a benign chronic phase to a
rapidly fatal blast crisis within three to fi,e years. he blast crisis is often preceded by an
accelerated phase in which increasing doses of hydro-yurea or busulfan are re;uired to lower
the neutrophil count. 0n contrast to the maturation of CML cells during the chronic phase$
during a blast crisis cells fail to mature and resemble the myeloblasts or lymphoblasts found
in patients with acute leukemias.
3.1.&. Differential Diagnose
Differential diagnose of CML include ?
+gnogenic Myeloid Metaplasia 3ith Myelofibrosis
Essential hrombocytosis
Myelodysplastic Byndrome
Myeloproliferati,e Disease
!olycythemia Cera
!roblems to be considered include the following?
+cute myeloid leukemia
Chronic myelomonocytic leukemia
Chronic neutrophilic leukemia
hrombocythemia
Leukemoid reactions from infections "chronic granulomatous 4eg$ tuberculosis5#
umor necrosis
3.1.). reatment
During the chronic phase of CML$ cytoreducti,e therapy is re;uired in most patients
to a,oid thrombotic complications that can result from high circulating le,els of neutrophils.
Aortunately$ CML cells are sensiti,e to se,eral oral chemotherapeutic drugs.
8inety percent of patients who are treated with hydro-yurea or busulfan ha,e
hematologic remissions. 7ydro-yurea is preferred to busulfan because the median duration of
the chronic phase and median sur,i,al were significantly better in a comparati,e trial of long/
term therapy to maintain the neutrophil count in the normal range .
7ydro-yurea is ad,antageous primarily because of its fa,orable to-icity profile rather than
because it has a specific effect on CML cells. reatment with either drug results in a
negligible rate of cytogenetic response and has no effect on the rate of progression to blast
crisis( therefore$ these treatments must be considered palliati,e.
Allogeneic Bone Marrow Transplantation
CML is a disease of hematopoietic stem cells. 7igh/dose chemotherapy that destroys
the leukemic cells also destroys normal bone marrow and therefore must be followed by
allogeneic bone marrow or stem/cell transplantation. Decades of follow/up data from
multiple centers ha,e confirmed that high/dose chemotherapy with busulfan and
cyclophosphamide or combined chemotherapy with cyclophosphamide and fractionated total/
body irradiation followed by allogeneic bone marrow transplantation is curati,e therapy in
patients with CML in chronic phase. he 0nternational .one Marrow ransplant <egistry and
the European Droup for .lood and Marrow ransplantation ha,e recently reported sur,i,al
rates of *' to &' percent among patients with CML in chronic phase who recei,ed
chemotherapy alone or radiotherapy plus chemotherapy followed by transplantation of
marrow cells from 7L+/matched sibling donors. he largest single/institution e-perience is
that of the Ared 7utchinson Cancer Center in Beattle$ which reports a sur,i,al rate of )'
percent at 1' years.
he success of allogeneic transplantation is age/dependent$ being significantly lower
in patients o,er the age of 9' years$ primarily because of higher treatment/related mortality.
+lthough age is clearly an important prognostic ,ariable$ transplantation decisions must be
considered indi,idually in the light of other ,ariables that influence outcome$ such as disease
stage and the le,el of donor1 recipient 7L+ matching. .ecause of the risk of transplantation/
related mortality$ it may be tempting to delay the procedure in patients with 7L+/matched
related donors until the disease progresses. his approach is inappropriate for two reasons.
Airst$ among patients with CML$ those who undergo transplantation when the disease
is in the chronic phase ha,e a higher likelihood of sur,i,al than do those who undergo
transplantation during the accelerated phase or blast crisis. Becond$ patients who undergo
transplantation within the first year after diagnosis ha,e a higher likelihood of sur,i,al than
do those who undergo transplantation later$ e,en if it is before progression to the accelerated
phase.
hese findings indicate that CML cells are capable of becoming resistant to high/dose
chemotherapy and radiotherapy. Di,en that CML progresses steadily to a more malignant
phenotype and that it is not possible to define the point in the chronic phase at which the
likelihood of sur,i,al tends to decrease$ allogeneic transplantation should be considered at
the time of diagnosis in eligible patients with 7L+/matched sibling donors. Enfortunately$
only 1* to 2' percent of patients with CML are candidates for allogeneic transplantation from
7L+/matched related donors because of age limitations and the low probability of ha,ing an
7L+/matched sibling donor. his number can be increased to 3' percent through the use of
7L+matched
unrelated donors identified by bone marrow1 donor registries.
7owe,er$ the sur,i,al rate among recipients of transplants from unrelated donors
identified by the 8ational Marrow Donor !rogram is substantially lower than that among
recipients of transplants from related donors. <ecent results from a Beattle study are better$
particularly in patients who were *' years of age or younger
who recei,ed a transplant matched for 7L+/+$ .$ and D<.1 by molecular studies.
Molecular typing allows a distinction to be made between subtypes of serologically related
but immunologically distinct 7L+ antigens. +lthough this strategy appears to impro,e
sur,i,al$ it will decrease the number of patients with CML for whom an appropriate donor
can be found.
3.1.:. !rognosis
+ follow/up on patients using imatinib published in the 8ew England Fournal of Medicine in
2''& showed an o,erall sur,i,al rate of :%2 after fi,e years.
435
0n 2'11$ an independent study
performed in :32 CML patients worldwide reported that the group of patients who achie,e a
stable cytogenetic response with imatinib shows an o,erall sur,i,al rate of %*.22 after :
years$ which is similar to the rate in the general population. @nly 12 of patients died because
of leukemia progression.
495
9.1. CLL
9.1.1. Definition
Chronic lymphocytic leukemia "CLL#$ the most fre;uent form of leukemia in 3estern
countries$ is characteri6ed by the clonal proliferation and accumulation of neoplastic .
lymphocytes in the blood$ bone marrow$ lymph nodes$ and spleen.
9.1.2. Etiology
Chronic lymphocytic leukemia "CLL# is a heterogeneous disease of unknown etiological
origin. CLL is the only . cell malignancy where a characteristic chromosomal translocation
is not in,ol,ed in cancer initiation. herefore$ the cause of tumorigenesis in CLL patients and
the type of cell that is transformed are two ;uestions that ha,e intrigued researchers for
decades. 7owe,er$ e,idence suggests the CLL cell may be deri,ed from ./1 cells. hese ./1
cells$ thought to de,elop during neonatal maturation as a link between innate and adapti,e
immunity$ share multiple phenotypic and genetic patterns with CLL cases. hese include
signaling molecules sensiti,ity and e-pression patterns$ ./cell receptor ".C<# specificity$
and a uni;ue immune/modulatory phenotype. hrough understanding the biological
rele,ance of ./1 cells in immune de,elopment and regulation$ we may further understand the
molecular mechanisms underlying the comple-ity of CLL. 3ith this understanding$ we can
pro,ide more optimal care to patients based on their uni;ue diagnosis and pathologic disease
course. 0n this re,iew$ based on our current understanding of CLL cells and .1 cells we
hypothesi6e that CLL cells are originated from .1 cells
.4*5
9.1.3. Epidemiology
CLL is a disease of older adults$ with a median age of )' years at the time of diagnosis.
4&5
hough less common$ CLL sometimes affects people between 3' and 3% years of age. he
incidence of CLL increases ,ery ;uickly with increasing age.
0n the Enited Btates during 2'12$ about 1&$'&' new cases are e-pected to be diagnosed$ and
9$*:' patients are e-pected to die from CLL.
4)5
.ecause of the prolonged sur,i,al$ which was
typically about ten years in past decades$ but which can e-tend to a normal life e-pectancy$
the pre,alence is much higher than the incidence.
CLL is ,ery rare in +sian countries$ such as Fapan and China$ and may account for as few as
1' percent of all leukemias in those regions.
4&5
Bubclinical GdiseaseG can be identified in 3.*2 of normal adults$
4:5
and in up to :2 of
indi,iduals o,er the age of )'. hat is$ small clones of . cells with the characteristic CLL
phenotype can be identified in many healthy elderly persons. he clinical significance of
these cells is unknown.
<ates of CLL are somewhat ele,ated in people e-posed to certain chemicals. Ender E.B.
Department of CeteransH +ffairs regulations$ Cietnam ,eterans who ser,ed in/country or in
the inland waterways of Cietnam and who later de,elop CLL are presumed to ha,e contracted
it from e-posure to Chemical 3eapons and may be entitled to compensation.
9.1.9. !athogenesis and !athophysiology
he molecular pathogenesis of CLL is unknown( there are no specific genetic abnormalities
and$ unlike other lymphoproliferati,e disorders$ balanced chromosomal translocations are
rare. Despite the absence of any common genetic alteration to all CLL patients$ se,eral
recurrent genetic defects ha,e been found in CLL cells. Esing A0B7$ chromosomal alterations
ha,e been found in appro-imately :'2 of CLL patients$ the most commonly occurring being
the deletion of 13;19$ the trisomy of chromosome 12$ the deletion of 11; and$ finally$ the
deletion of 1)p$ which seems to clearly influence the choice of specific treatment. 0t has been
repeatedly demonstrated that patients with the 1)p deletion respond poorly to most drugs
used routinely in the treatment of this disease.
.esides the presence or absence of specific genetic aberrations$ se,eral pieces of e,idence
point to a key role of the microen,ironment in the sur,i,al of leukemic cells. CLL cells
rapidly undergo spontaneous apoptosis when cultured ex vivo$ suggesting that the
microen,ironment found in specific anatomic locations$ particularly bone marrow and lymph
nodes$ plays an important role in the regulation of death and proliferation of neoplastic cells.
+ntigenic stimulation through the ./cell receptor ".C<# also has a central role in promoting
the sur,i,al of CLL cells. Moreo,er$ CLL cells ha,e stereotyped .C<s$ using
immunoglobulin hea,y/chain ,ariable gene families in a restricted distribution. his
phenomenon suggests that CLL cells recogni6e common antigens$ and that these antigens
ha,e an important role in the de,elopment and progression of the disease.
9.1.*. Clinical Manifestation and Diagnosis
he median age of patients at diagnosis is &* years$ with only 1' to 1* percent under *' years
of age. 0n most series$ more men than women are affected. he course of the disease is
,ariable. 3hereas some patients with CLL ha,e a normal life span$ others die within fi,e
years after diagnosis. During the past few years$ important ad,ances ha,e been made in the
understanding of the biology$ natural history$ and treatment of CLL.
he hallmark of CLL is an increased white/cell count with about %* percent small
lymphocytes. o make the diagnosis$ careful re,iew of a good/;uality peripheral/blood smear
is thus essential. +ccepted re;uirements for diagnosis include absolute lymphocytosis$ with
most lymphocytes being small and mature in appearance( a characteristic immunophenotype
of the lymphocytes "i.e.$ low/density surface/membrane immunoglobulin$ Cd*I$ CD1%I$
CD2'I$ CD23I$ AMC)/=I$ and CD22/=I#( and infiltration of the bone marrow by
lymphocytes. +lthough diagnostic thresholds for both lymphocytosis and bone marrow
infiltration ha,e been proposed$ these are arbitrary. CLL can be diagnosed whene,er there is
an absolute increase in lymphocytes in blood and their morphology and immunophenotype
ha,e the characteristic features of the disease. he Arench1+merican1.ritish classification
system proposed three morphologic types based on the proportion of atypical lymphocytes in
blood? typical CLL$ in which more than %' percent of the lymphocytes are small( CLL1
prolymphocytic leukemia$ in which the proportion of prolymphocytes is between 11 and *9
percent( and atypical CLL$ in which there is a heterogeneous lymphoid/cell morphology but
the proportion of prolymphocytes is less than 1' percent. +gain$ these criteria are arbitrary.
+lthough there are atypical cases of CLL$ other lymphoproliferati,e disorders should be
carefully considered before atypical CLL is diagnosed. 0n this regard$ analysis of the
immunophenotype of the neoplastic . cells$ as well as cytogenetic and molecular data$ may
be useful. +typical lymphoid/cell morphology$ for e-ample$ is more fre;uent in patients with
trisomy 12. @n the other hand$ prolymphocytic leukemia should not be regarded as a ,ariant
of CLL but as a separate entity that is characteri6ed by a high white/cell count with a
predominance of prolymphocytes in blood "i.e.$ J*9 percent# with a typical phenotype "i.e.$
surface/membrane immunoglobulinII$ CD1%I$ CD2'I$ CD23/=I$ AMC)I#$ splenomegaly$
resistance to therapy$ and poor outcome. his is in contrast with CLL1prolymphocytic
leukemia$ in which the clinical features and immunophenotype are much closer to those of
CLL.
9.1.&. Differential Diagnose
Differential diagnose of CLL include
+cute Lymphoblastic Leukemia
7airy Cell Leukemia
Lymphoma$ Diffuse Large Cell
Lymphoma$ Aollicular
Lymphoma$ Lymphoblastic
Lymphoma$ Mantle Cell
Lymphoma$ 8on/7odgkin
Bmall Lymphocytic Lymphoma
/!rolymphocytic leukemia "Aormer /CLL#
9.1.). reatment
he diagnosis of CLL does not imply the need for therapy. + number of indications Kustify
treatment in CLL$ including constitutional symptoms$ bulky lymphadenopathy$ and
splenomegaly causing compressi,e problems( howe,er$ prognostic factors are the most useful
tools in decisions about therapy in a gi,en patient.
+t present$ there is no curati,e therapy for CLL. his$ coupled with the potentially indolent
course of the disease and the ad,anced age of many patients$ makes palliation of symptoms
and prolongation of sur,i,al reasonable therapeutic goals in most patients with CLL re;uiring
therapy. 7owe,er$ in younger patients with poor/risk factors$ e-perimental approaches aimed
at achie,ing cure are warranted. Current treatment possibilities according to prognostic
factors and other ,ariables are discussed below.
Early and Stable Disease
!atients with early$ stable CLL should not be treated unless symptoms de,elop or the disease
progresses. his strategy is based on two kinds of e,idence. Airst$ patients with early and
stable disease may sur,i,e as long as normal subKects of the same age. Becond$ treatment of
patients in an early stage ".inet stage + or <ai stage '# with chlorambucil$ either
continuously or intermittently$ delays the rate of disease progression but does not increase
sur,i,al. Moreo,er$ in one study continuous treatment with chlorambucil was associated with
a shorter sur,i,al because of the high incidence of epithelial cancers.
Advanced CLL with a Large Tumor Burden and Bone Marrow Failure
Chlorambucil "e.g.$ at a dose of & to : mg orally daily( '.9 to '.: mg per kilogram of body
weight orally e,ery two weeks# should be still considered the standard treatment. reatment
is gi,en as long as the patient responds$ usually for no less than : to 12 months. <esponse
rates range from 9' to )' percent$ but complete responses are rare. 0n recent trials$ the
combination of chlorambucil and prednisone has not yielded better results than treatment
with chlorambucil alone. +lthough patients treated with combination/chemotherapy regimens
ha,e higher response rates$ sur,i,al is not prolonged.
he role of maintenance treatment in CLL has ne,er been e-tensi,ely in,estigated. Esually$
treatment is discontinued once a response has been achie,ed and is restarted when there is
disease progression. 0n most instances$ renewed treatment results in a poorer response than
initial treatment$ probably because of the o,ere-pression of mdr genes and p*3 gene
mutations. Aor patients with no response to standard therapy or a relapse after such therapy$
purine analogues$ particularly fludarabine$ are the treatment of choice .
Cytopenias Due to an mmune Mechanism or !ypersplenism
!atients with cytopenias due to an immune mechanism should be treated with a
corticosteroid$ with cytoto-ic agents added only if there is no response after four to si- weeks
of treatment. +lternati,e treatments include high/dose immune globulin$ cyclosporine$
splenectomy$ and low/dose radiation to the spleen.he latter two approaches may also be
useful in cases of hypersplenism. <arely$ pure red/cell aplasia may be associated with CLL.
E-cellent treatment results ha,e been reported with cyclosporine.
Treatment o" Systemic Complications
7ypogammaglobulinemia is fre;uent in CLL and is the chief cause of infections. 0n a
randomi6ed study$ high/dose immune globulin "9'' mg per kilogram intra,enously e,ery
three weeks# pre,ented infections but had no effect on sur,i,al. Cost1benefit considerations
make the routine use of immune globulin in all patients with hypogammaglobulinemia
debatable. Lower doses of immune globulin "i.e.$ 2*' mg per kilogram e,ery four weeks or
1' g e,ery three weeks# may be as effecti,e as high doses. 0nfections ha,e to be treated with
broad/spectrum antibiotics$ and clinicians must keep in mind the possibility of opportunistic
infection. Caccines are considered to produce a suboptimal response because the immune
system is impaired. <ecombinant hematopoietic growth factors "e.g.$ granulocyte1
macrophage colony/stimulating factor and granulocyte colony/stimulating factor# may
o,ercome neutropenia related to treatment. Ainally$ erythropoietin may be useful to treat
anemia that is unresponsi,e to other measures.
#ew Treatment Approaches
$urine Analogues
!urine analogues "pentostatin 42H/deo-ycoformycin5$ fludarabine$ and 2/
chlorodeo-yadenosine# are highly acti,e against CLL. heir mechanisms of action are
comple-$ but include the induction of apoptosis. Aor patients with no response to initial
therapy$ fludarabine "2* mg per s;uare meter of body/surface area intra,enously for fi,e days
e,ery four weeks# is the treatment of choice$ with a response rate ranging from 1) to )9
percent "rate of complete response$ ' to 2' percent#. he response rates are higher in patients
who responded to pre,ious therapies and who ha,e not had e-tensi,e treatment. !reliminary
results of ongoing trials comparing fludarabine with combinations of cyclophosphamide$
do-orubicin$ ,incristine$ and prednisone and cyclophosphamide$ do-orubicin$ and prednisone
show a higher response rate for fludarabine( whether this will translate into longer sur,i,al
remains to be seen.
he main to-ic effect of purine analogues is myelosuppression( acute tumor lysis syndrome
and autoimmune hemolytic anemia ha,e also been documented. @pportunistic infections
"e.g.$ cytomegalo,irus$ to-oplasma$ Pneumocystis carinii, legionella$ and listeria# occur
because of the decrease in CD9I cells induced by these agents. .ecause patients treated with
purine analogues and prednisone ha,e more opportunistic infections than those treated with
purine analogues alone$ prednisone should be omitted from regimens containing purine
analogues. +lthough there is no proof of their effecti,eness$ oral antibiotics can be used as
prophyla-is.
he role of purine analogues in untreated patients is being in,estigated. !reliminary results
show rates of complete response ranging from 2* to )9 percent for fludarabine and 2/
chlorodeo-yadenosine. !entostatin has been in,estigated less thoroughly. + E.B. trial
comparing chlorambucil with fludarabine as first/line therapy has recently completed the
accrual of patients$ but no data are yet a,ailable.
8ew treatment possibilities may allow the achie,ement of remission at the molecular le,el.
herefore$ to e,aluate patientsH responses to therapy$ in addition to standard
clinicohematologic methods$ cytofluorometry and molecular/biology techni;ues are needed.
his information may be useful in planning treatment strategies such as autotransplantation.
+lthough in the future fludarabine or other purine analogues will probably replace
chlorambucil as standard therapy in CLL$ for now such an approach should be confined to
clinical trials. Ainally$ the role of purine analogues in combination with other cytoto-ic agents
"e.g.$ cyclophosphamide# or biologic/response modifiers "e.g.$ interferon# is being
in,estigated.
Transplantation o" !ematopoietic $rogenitors
Data on the largest series of allotransplantations$ in,ol,ing *9 patients$ ha,e been collected
by the European and 0nternational .one Marrow ransplant <egistries "Michallet M$ et al.?
unpublished data#. he median age of the patients at transplantation was 91 years "range$ 21
to *)#. .efore transplantation most patients recei,ed a conditioning regimen consisting of
cyclophosphamide and total/body irradiation as well as cyclosporine and methotre-ate as
prophyla-is against graft/,ersus/host disease. @f the *9 patients$ 3: ")' percent# entered
remission and 29 "99 percent# were ali,e a median of 2) months "range$ * to :'# after
transplantation. he probability of sur,i,al at three years was 9& percent "%* percent
confidence inter,al$ 32 to &' percent#. Ai,e patients died of progressi,e leukemia "% percent#
and 2* of treatment/related complications "9& percent#. his contrasts with the 1' percent
mortality rate reported in recent studies from single institutions( the difference is probably
due to differences in patient/selection criteria. he results are better in patients with stable
disease that is responsi,e to therapy than in those with progressi,e disease. <elapses$
sometimes as late as four years after transplantation$ may occur.
here are se,eral reports on autotransplantation in CLL. +bout 9' patients ha,e been
described. +ll the patients had ad,anced disease before transplantation$ and all recei,ed
cyclophosphamide and total/body irradiation as part of the conditioning regimen. 0n about
half the patients the bone marrow graft was purged with monoclonal antibodies against .
cells "CD1%$ CD2'$ CD1'$ and CD*#. he follow/up is too short to draw conclusions.
+lthough results are promising$ transplantation should still be considered an e-perimental
procedure. @pportunistic infections "e.g.$ to-oplasmosis# are an additional concern.
ransplantation$ howe,er$ should be considered in any young patient with high/risk CLL.
Biotherapy
0nterferon alfa does produce a response$ albeit not a complete response$ in patients with early
disease who ha,e not recei,ed prior therapy. hus$ it might potentiate the responses achie,ed
with chemotherapy. he effecti,eness of monoclonal antibodies$ either alone "e.g.$
C+M!+7 1/7# or conKugated with to-ins "e.g.$ .9/blocked ricin#$ cytoto-ic agents$ or
radioisotopes "e.g.$ iodine/131#$ is being in,estigated( the response obtained is usually partial
and transient. Monoclonal antibodies might be useful as a treatment for minimal residual
disease. 0nterleukins "e.g.$ interleukin/2$ 9$ and &# are under study. 0nterleukin/2 has pro,ed to
ha,e limited clinical acti,ity and substantial to-icity at high doses. !reliminary e-periments
in mice suggest that antisense oligonucleotides specific for interleukin/1'$ a potent stimulator
of the growth of neoplastic . lymphocytes$ might be clinically useful.
9.1.:. !rognosis
0n se,eral recent series$ the median sur,i,al of patients with CLL was about nine
years$ although indi,idual sur,i,al ,aries. Clinical stages$ bone marrow histopathological
findings$ blood lymphocyte counts$ lymphocyte doubling time$ and cytogenetic abnormalities
are good predictors of sur,i,al. 0n addition$ blood lymphocyte morphology( serum
concentrations of lactate dehydrogenase$ thymidine kinase$ beta
2
/microglobulin$ CD23$ and
CD2*( and the presence of p*3 mutations ha,e been found to be of prognostic ,alue in some
studies ransformation of the disease into large/cell lymphoma "<ichterHs syndrome# carries a
poor prognosis$ with a median sur,i,al of less than one year after its appearance. Bimilarly$
CLL1prolymphocytic leukemia has a poorer prognosis than classic CLL. Ainally$ a response
to therapy is associated with longer sur,i,al.
Clinical staging systems are easy to use$ and their prognostic ,alue has been widely ,alidated.
7owe,er$ they do not pro,ide information on the likelihood of progression in a gi,en patient.
0n this regard$ other ,ariables may pro,ide prognostic information. Aor e-ample$ among
patients with early/stage CLL$ those with a pattern of diffuse infiltration of bone marrow on
histopathological analysis or rapidly increasing lymphocyte counts "or both# are likely to
ha,e progression and shorter sur,i,al$ whereas those without diffuse infiltration of bone
marrow and with low$ stable blood lymphocyte counts usually ha,e an indolent$
nonprogressi,e$ smoldering disease.
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