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Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

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Published by: hemendre on Sep 02, 2010
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Chronic Myeloid Leukemia
N Singhal*, PP Bapsy**, KG Babu***, J George*
Chronic myeloid leukemia is one of the commonest hematological malignancies seen in clinical practice.It is the result of abnormal and excess cell proliferation due to de-regulated bcr-abl tyrosine kinaseactivity as a result of Philadelphia chromosome. The present article discusses the various options availableto treat the disorder. Allogeneic stem cell transplant remains the gold standard and the only curativeoption. Hydroxyurea and Busulfan helps in controlling the total leukocyte count but fail to impact onsurvival. Interferon especially when combined with cytarabine is curative in minority of patients thougha substantial number of patients achieve functional cure. Imatinib, a molecular targeted oral therapy,against bcr-abl tyrosine kinase is the latest addition to various treatment options. Early results appearvery promising and can be considered as non- transplant standard of care.
hronic myeloid/myelogenous leukemia (CML) is a clonalmyeloproliferative disorder of pluripotent stem cellaffecting myeloid, erythroid, megakaryocyte, B and some timeT lymphoid cells. It accounts for 50-70% of leukemias in India
with an annual incidence of 1-2/ lack population. The medianage of presentation is 50 years. The patient generally presentswith progressive granulocytosis, marrow hypercellularity andsplenomegaly. In recent times, asymptomatic presentation isseen quite often. Untreated the disease typically passesthrough three phases - chronic phase (approximate duration:3-5 years), accelerated and blast phase (approximate duration:3-6 months) ultimately terminating fatally.The diagnostic hallmark of CML is Philadelphiachromosome (Ph) which results from a balanced translocationbetween the long arms of chromosomes 9 and 22 [t 9; 22(q34;q11)], resulting in bcr/abl chimeric gene that expresses anabnormal fusion protein with deregulated tyrosine kinaseactivity. Ph chromosome can be detected in 95% cases of CML by conventional cytogenetics and the remaining 5%patients have gene product of Ph chromosome i.e. bcr-ablthat can be detected by PCR. The deregulated bcr-abl tyrosinekinase phosphorylates a host of intracellular substrates,which results in activation of downstream signal transductionpathways resulting in unregulated and excessive proliferationof cells. (Table 1)The present article aims at delineating the varioustreatment options available to a patient with CML and
*Resident; **President and HOD; ***Associate Professor, Departmntof Medical Oncology, Kidwai Memorial Institute of Oncology,Bangalore 560029.Received : 3.10.2003; Revised : 6.2.2004; Accepted : 1.4.2004
highlights the shifting paradigm which the malignancy hasseen with the introduction of targeted molecular therapy. Wewill also try to find out how best to integrate the varioustreatment options into the treatment decision-making processfor a patient newly diagnosed with CML.The treatment of CML can be divided into transplant andnon-transplant modalities. Since the transplant still remainsthe gold standard, it will be discussed first followed by anoverview of non-transplant modalities (Table 2).
Table 1 : Pathogenesis of CML
BCR-ABL increases CRK-L which decreases stromal-clonal celladhesion. Activation of RAS leads to increase proliferation. Decreasedlevels of BAD (apoptotic protein), increased levels of BCL (antiapoptotic protein) and IAP (inhibition of apoptosis protein) leads todecreased levels of cytochrome-c, caspase 3,9 (apoptotic protein)which leads to decreased apoptosis (reference 2).
JAPIVOL. 52MAY 2004www.japi.org411
Introduced in 1970s, allogeneic stem cell transplant (ASCT)has established itself as the only curative option as far as thetreatment of CML is concerned. The procedure entailseradicating the host marrow and suppressing the hostimmunity with supra doses of chemotherapy (preparatoryregimen) followed by infusion of donor stem cells which willtake over the function of myelopoiesis and immunereconstitution. Eradication of leukemia depends to a largedegree on donor lymphocyte mediated graft versus leukemia(GVL) effect. The efforts are on to decrease the intensity of preparatory regimen and to rely more on GVL effect for curingCML (reduced intensity or mini transplant or non-myeloablative transplant). This hopefully will decrease thetreatment-related mortality (TRM) and thereby increasing thesurvival. With conventional transplant, in chronic phase,projected 5 years survival ranges between 50-60%. Relapsesoccur in approximately 15-30% cases and are commonly seenwith in the first 5 years. Procedure-related mortality is around10-40%.
Transplant performed in blast phase is unsatisfactorywith survival less than 10%. Intermediate survival of 25-35%is reported for ASCT in accelerated phase. Increased relapserate and increased TRM accompany ASCT in transformedphases.Outcome following ASCT not only depends on the phaseof disease but a host of other factors are also important.1.
: Patients have a continuous and inverse relationshipbetween age and survival. Older patients do worsemainly because of an increased TRM; relapse rates arealmost similar. In IBMTR (international bone marrowtransplant registry) data, patients above 50 years hadsurvival of 30% as compared to younger patients in whomsurvival of 60-70% is expected.2.
Timing of transplant 
: As the disease progresses theoutcome of transplant worsens. Hence ASCT is performedwithin 1-2 years of diagnosis of CML.3.
Pretransplant treatment 
: Patients treated with Busulfanbefore ASCT have worse outcome. Prior therapy withhydroxyurea or interferon does not appear to affectoutcome.
Preparatory regimen
: Conventional ASCT usescyclophosphamide with busulfan or total body irradiationas conditioning regimen. With the recognition of importance of GVL effect, a number of centres haveattempted to use reduced intensity regimen. Howeverthere is disagreement to what constitutes reducedintensity regimen. Various combinations that have beentried are cyclophosphamide and fludarabine with orwithout antithymocyte globulin and fludarabine withmelphalan.5.
GVHD (graft versus host disease) prophylaxis
: DonorT-lymphocytes mediated reaction in host generalmanifests as diarrhea, elevated liver enzymes, fever andcutaneous changes. Acute GVHD
seen in first 100 daysoccurs in 8-63% and causes death in around 13% cases.Chronic GVHD (after 100 days) is seen in upto 75% caseswith a mortality of upto 10%.
Methotrexate andcyclosporine is commonly used for GVHD prophylaxis.With reduced intensity conditioning regimens choice of GVHD prophylaxis has been cyclosporine alone.Attempts to decrease intensity of GVHD have beenfraught with increased treatment failure. Anotherapproach to abrogate GVHD is to use T lymphocytedepleted allogeneic marrow, but it increases risk of non-engraftment, risk of relapse and delays immunereconstitution.
6.Relatedness of donor: With scarcity of HLA matchedsibling donor attempts have been made to use HLAmatched transplant from unrelated donors (MURD). Butthese grafts are associated with increased TRM andmorbidity. Graft failure, severe and extreme acute andchronic GVHD contributes to it. Matching at HLA DR81locus is most important. Ideal patients for MURD arepatients with age less than 30 years, early chronic phase,CMV negative and having received non-T cell depletedmarrow infusions.
Such patients can be expected to havea 2 years survival of 51%, a TRM of 47% and relapse rateof 2%.Gratwohl
analysed the data from EBMTR (European BoneMarrow Transplant Registry) and came up with 5 factor risk score for individual transplant procedure. For each factor apatient can have a score from 0 to 2 and the aggregate scorecorrelates well with survival. This approach is extremely usefulfor helping clinicians to make recommendations and thepatients to decide whether or not to undergo ASCT (Table 3).
Recognition and management of relapse
Incidence of relapse within first 5 years in chronic phaseranges between 0-30%. The majority of relapses occur within the first 4 years post ASCT. Relapses normally proceed inan orderly manner with molecular relapse progressing tocytogenetic and eventually hematologic relapse. The bestoption for these patients is original donor lymphocyte
Table 2 : Criteria for hematologic, cytogenetic andmolecular remissions in CML
* Complete hematologic response(CHR)
1.WBC<10,000/µl2.Platelets <450,000/µl3.No immature cells-blasts, promyelocytes or metamyelocytes
* Partial hematologic response(PHR)
As per CHR except1.Persistence of immature cells2.Platelets <50% pretreatment level but >450,000/µl3.Persistent splenomegaly but <50% of pretreatment level
* Cytogenetic response(CYGR) (requires evaluation of minimum of 20 metaphases)
Complete : no Ph+ cell in bone marrow metaphasesPartial : 1-34% Ph+ cell in bone marrow metaphasesMinor : 35-90% Ph+ cell in bone marrow metaphasesMajor : complete plus partial CYGR
* Minimal residual disease(MRD) +
Persistence of bcr-abl as detected by RT-PCR
infusion in an escalating dose manner.
The other optionsinclude 2nd transplant using same donor, STI 571 or IFN
Overall contribution of allografting to cure of CML
Data from Goldman shows that out of total cohort of CMLpatients, 55% are ineligible for ASCT because of age morethan 55 years. Of the remaining 45%, 15% patients do nothave any donor. Remaining 30% have either HLA identicalsibling or unrelated donor and undergo transplant with curerate of approximately 10% and 8% respectively. So transplantcan be offered to 30% patients with CML and 18% of totalcohort is cured by transplant.
This leaves roughly more than 70% patients who will becandidate for various forms of non-transplant treatmentmodalities.
Non-transplant treatment
Historically CML was treated with splenic irradiation, P
,splenectomy and arsenicals.
Busulfan was the first cytotoxic agent introduced for thetreatment of CML is 1950s. Busulfan is given in the dose of 0.1mg/kg/day per-orally with 50% dose reduction withreduction of WBC count by 50%. Drug is discontinued whencounts reach less than 20000/µl. Over the years, the use of busulfan has fallen out of favour due to adverse events aspulmonary fibrosis, rash, hypoadrenalism, severe andprolonged marrow aplasia and poor ASCT outcome. Currentlybusulfan use is limited to the patients who are intolerant tohydroxyurea.
Hydroxyurea (OH-urea), a ribonucleotide reductaseinhibitor was introduced in 1970s. It has the advantage of modest side effect profile, rapid onset of action and rapidrecovery if excessive lowering of WBC occurs. Dose of OH-urea varies as per WBC counts and it is recommended tomaintain WBC between 20-30000/µl (Table 4).OH-urea does not affect transplant outcome and can begiven in pregnant females. Major problem with OH-urea usageis difficulty in sustaining normal WBC counts.A prognostic score was developed by Sokal
et al
forpatients treated with OH-urea, and the patients can be dividedinto low, intermediate and high risk (Table 5).Both hydroxyurea and busulfan can be used for controllingcounts and splenomegaly but the cytogenetic response isexceptional and thus no meaningful survival advantage canbe achieved. These drugs do not alter the natural history of CML.
Introduction of IFN-
in mid 1980 was the first non-transplant modality that was shown to prolong survival overOH-urea and busulfan by 1-2 years. Exact mechanism of actionthough unknown is considered apoptosis, differentiation andantiangiogenesis. It eliminates the deficient inhibitory stroma- cell progenitor interaction in CML. Drug is more effective inthe early chronic phase rather than late chronic phase andineffective in accelerated or blast phase. In chronic phasemajor CYGR can be achieved in around 18% of the patientsand complete CYGR in less than 5%. Interferon has shownsurvival benefit when compared to hydroxyurea or busulfan(57% vs. 46%/34%).
Addition of low dose cytarabine to IFN
Table 3 : Risk score for individual transplant procedure
FeatureScoreA.Donor typeHLA identical sibling 0Unrelated/non-identical1B.Stage of diseaseChronic0Accelerated1Blast2C.Age< 20 years020 - 40 years1> 40 years 2D.Donor/recipient sex combinationOther 0Female donor for male recipient1E.Interval from diagnosis to treatment< 12 months 0> 12 months1
Table 4 : Rough guide to Hydroxyurea dosage
WBC count (/µl)Dose< 10,000500mg10-20,0001gm20-30,0001.5gm30-50,0002 gm50-80,0003 gm80-100,0004 gm> 1 Lac5 gm
Table 5 : Prognostic index for patients treated withHydroxyurea and Interferon
Age (years)0.0116 (age - 43.4)0.6666 when aged
50Spleen (below costalmargin) (cm)0.0345 (spleen - 7.51)0.042 x spleenPlatelet x 10
/L*0.188 [(platelet)
/1.0956, when
1500700 - 0.563]Myeloblast %*0.08870.0584 x myeloblast(myeloblast - 2.10)Eosinophils %*0.0413 x eosinophilsBasophils %*0.2039 when basophils
3%Relative riskexponential of totalTotal x 1000*% in peripheral blood,SokalEuroLow<0.8
780Intermediate0.8 - 1.2781 - 1479High> 1.2

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