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Journal of Clinical Oncology, Vol 18, Issue 20 (October), 2000: 3513-3521
© 2000 American Society for Clinical Oncology

Homoharringtonine and Low-Dose Cytarabine in the Management of Late Chronic-Phase Chronic Myelogenous Leukemia

By Hagop M. Kantarjian, Moshe Talpaz, Terry L. Smith, Jorge Cortes, Francis J. Giles, Mary Beth Rios, Susie Mallard, James Gajewski, Anthony Murgo, Bruce Cheson, Susan O’Brien

From the Departments of Leukemia, Bioimmunotherapy,Biostatistics, and Blood and Bone Marrow Transplantation,M.D. Anderson Cancer Center, Houston, TX; and the National CancerInstitute, Bethesda, MD.

Address reprint requests to Hagop M. Kantarjian, MD,Department of Leukemia, Box 61, M.D. Anderson Cancer Center, 1515Holcombe Blvd, Houston, TX 77030; emailhkantarj{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTSAND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: : To evaluate the efficacy andtoxicity profiles of a combination regimen of homoharringtonine (HHT)and low-dose cytarabine (ara-C) in patients with Philadelphiachromosome (Ph)–positive chronic myelogenous leukemia (CML) whohad experienced treatment failure with interferon alfa (IFN{alpha})therapy.

PATIENTS AND METHODS: One hundred five patients were treated: 100 in chronicphase (15 with cytogenetic clonal evolution) and five in acceleratedphase. Their median age was 52 years; all had been treatedunsuccessfully with IFN{alpha}; 94% were in late chronic phase; 43% hadbeen exposed to ara-C and 11% had been exposed to HHT. Patientsreceived HHT 2.5 mg/m2 by continuousinfusion daily for 5 days and ara-C 15mg/m2 daily in two subcutaneous injectionsfor 5 days every 4 weeks. The outcome of the 100 patients in chronicphase was compared with a previous study group of 73 patients treatedwith HHT alone.

RESULTS: Overall, the complete hematologic response (CHR) rate in chronic phasewas 72%; the cytogenetic response rate was 32% (major response, 15%;complete response, 5%). Toxicities were acceptable, mostly related tomoderate diarrhea (3%), headaches (3%), cardiovascular events (3%),and myelosuppression-associated complications (3% to 14%). With amedian follow-up period of 25 months, the estimated 4-year survivalrate was 55%. Response rates were identical with HHT plus ara-C versusHHT alone, but the survival was significantly longer with thecombination after accounting for differences in the study groups andby multivariate analysis.

CONCLUSION: The combination regimen of HHT and ara-C is effective andsafe in patients with CML who have experienced treatment failure withIFN{alpha} and needs to be investigated together with IFN{alpha} as partof front-line CML therapy. The addition of ara-C did not improve theresponse rates but may have improved survival, perhaps throughsuppression of clones related to diseasetransformation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTSAND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
SURVIVAL IN Philadelphia chromosome (Ph)–positivechronic myelogenous leukemia (CML) has improved with interferon alfa(IFN{alpha}) therapy and allogeneic stem-cell transplantation(SCT).1-4 With IFN{alpha} regimens, the median survival is6 to 7 years. Prognosis is associated with patient riskgroup,5,6 doseschedules of IFN{alpha}, combined therapies (eg, with low-dosecytarabine [ara-C]),7-9 and the achievement and degree ofPh-suppression (cytogenetic response). By multivariate and landmarkanalyses, achievement of cytogenetic and major cytogenetic responses(Ph-positive metaphases < 35%) have been associated independentlywith survival prolongation.8-12

Improving on the state and duration of minimal diseaseburden (complete hematologic or cytogenetic response) in CML, as inother cancers, has become the target of many investigationalstrategies and a surrogate end point for long-termsurvival. Discovering agents or modalities that may suppressPh-positive cells is thus actively pursued. Patients who fail IFN{alpha}regimens and who are not eligible for allogeneic SCT have the optionof receiving hydroxyurea therapy or undergoing investigationalapproaches such as autologous SCT or new agents.

Homoharringtonine (HHT), a plant alkaloid, was firstinvestigated in China and reported to be active in leukemias.13,14 Phase I and II studiesin the United States confirmed its antileukemic activity butdocumented a high incidence of cardiovascular complications withshort-infusion schedules15,16 and with higher-dose continuous-infusionschedules (30% incidence of hypotension and arrhythmias).17 However, definite activity wasobserved in acute myelogenous leukemia (AML), acute promyelocyticleukemia (APL), and myelodysplastic syndrome (MDS).17-20 We hadinvestigated a lower-dose, longer-duration, continuous-infusionschedule of HHT (2.5 mg/m2 daily for 10 to14 days instead of 5 to 9 mg/m2 daily for 5to 7 days). This schedule abrogated the occurrence of cardiovascularcomplications including hypotensive events and arrhythmias, whichoccurred in less than 5% of patients with the new schedule.20 This observation, together with thenoted antiproliferative effect of HHT, resulted in further studies ofthe new schedule in CML, an indolent disease that requires a safeschedule for long-term therapy. We subsequently reported on theefficacy of HHT alone in patients with late chronic-phase CML(duration of disease more than 12 months), many of whom wereIFN{alpha}-resistant, and in sequence with IFN{alpha} in earlychronic-phase CML.21,22 In both studies, significant anti-CMLefficacy was observed.

ara-C has shown activity in CML as a single agent and incombination with IFN{alpha}.23-25 The mechanisms underlying the anti-CMLefficacy of HHT are unknown but may be mediated through an effect onthe apoptosis pathways.26,27 HHT had also been reported to besynergistic with IFN{alpha} and with ara-C in preclinicalmodels.27 The limitedtherapeutic options of patients with late chronic-phase CML whoexperience treatment failure with IFN{alpha} therapy and who are notcandidates for allogeneic SCT and the efficacy of both HHT and ara-Cin vitro26-28 and in vivo21-25 led to thecurrent investigation of HHT and low-dose ara-C combination inpatients who have failed IFN{alpha} regimens. The results are summarizedin thisstudy.


   PATIENTSAND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTSAND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Group
Adults with a diagnosis of Ph-positive CML were enteredonto the study after informed consent was obtained. Eligibilitycriteria were as follows: (1) age 15 years or older, (2) chronic- oraccelerated-phase CML disease,29 (3) good performance status (Zubrod0 to 2), (4) treatment failure on an IFN{alpha}-containing regimen, (5)normal renal (creatinine < 2 mg/dL) and hepatic functions(bilirubin < 2 mg/dL), and (6) no evidence of severe cardiacdisease (class III or IV).

Treatment failure of IFN{alpha}-containing regimens wasdefined in one of three categories: (1) hematologic resistancereferred to failure to achieve at least a partial hematologic response(PHR) after 3 months or more of therapy, failure to achieve a completehematologic response (CHR) after 6 months or more of therapy, or lossof hematologic response after achieving CHR, with an increasing WBCcount greater than 12 x 109/L onoptimal IFN{alpha} therapy documented for at least 4 weeks; (2)cytogenetic resistance referred to failure to obtain a cytogeneticresponse (Ph-positive cells >= 90%) after 12 months or more oftherapy, or loss of cytogenetic response with return of Ph-positivecells to greater than 90%; and (3) severe grade 3 or 4 unacceptabletoxicity related to IFN{alpha} therapy. For hematologic or cytogeneticresistance, patients were required to have received IFN{alpha} at 5million U/m2 daily or the maximum-tolerateddose. The median IFN{alpha} dose delivery in our studies was 5 millionU/m2 daily with IFN{alpha} alone and morethan 3 million U/m2 daily with IFN{alpha}combinations. In the category of failure because of unacceptableIFN{alpha}-associated toxicity, no minimum dose or duration of therapywas specified, because some of these toxicities may not bedose-related and are life-threatening (eg, immune-mediatedthrombocytopenia, immune-mediated hemolysis, neurotoxicity, severedepression, cardiomyopathy, pulmonary failure, and so on).

Patients in blastic phase were not eligible (marrow orperipheral blasts >= 30%). Patients with cytogenetic clonalevolution as their only accelerated-phase feature were included in thechronic-phase analysis on the basis of their more favorable prognosisfrom previous analyses.30,31 Late chronic phase of CML was defined astime from diagnosis to start of therapy of more than 12months.1,2,6,9,25

Characteristics of the study group are listed inTable 1. Theirmedian age was 52 years; 49% were females. All patients had previouslyreceived IFN{alpha} therapy; 54% were referred from outside theinstitution having experienced treatment failure with IFN{alpha}.IFN{alpha} treatment failure was attributed to hematologic resistance(42 patients), lack of cytogenetic response after 12 months or more ofIFN{alpha} (25 patients), severe unacceptable toxicity with IFN{alpha} (18patients), resistance plus toxicity (16 patients), or other reasons(four patients). All 25 patients entered for lack of cytogeneticresponse had IFN{alpha} therapy discontinued and had evidence of activeCML disease (leukocytosis, thrombocytosis) at the time of initiationof HHT and ara-C therapy. Only six patients received therapy with aCML chronic-phase duration of less than 12 months: five had IFN{alpha}therapy discontinued because of severe toxicities (two of them withresistance) and one because of hematologic resistance. Elevenpatients had previously received HHT on the front-line sequential HHTfollowed by IFN{alpha} maintenance (DM91-13)22; 45 patients had previously receivedara-C with IFN{alpha}.


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  		Table 1. Characteristics of the Study Group (105 patients)
 
All 105 patients had 95% to 100% Ph-positive metaphases atthe start of HHT and ara-C therapy. One hundred patients were inchronic phase, 15 of whom had cytogenetic clonal evolution. Thisincluded trisomy 8 (two patients), double Philadelphia (one patient),isochromosome 17 (one patient), and other abnormalities (11patients). Five patients had accelerated phase CML (basophilia >=20%, two patients; blasts >= 15%, one patient; thrombocytopenia <100 x 109/L, twopatients).

Therapy
HHT was given at a dose of 2.5mg/m2 by continuous infusion daily for 5days (days 1 to 5) together with ara-C 15mg/m2 daily in two equal subcutaneous doses12 hours apart for 5 days (days 1 to 5). HHT was given either througha central-line catheter or through a peripheral-line catheter replacedevery 2 to 3 days. Therapy was repeated every 4 weeks. HHT and ara-Ctherapy was modified to achieve with each course a lowest granulocytecount of approximately 109/L, with aplatelet count greater than 50 x109/L. For this purpose, the modificationsin therapy were in the duration of treatment, ie, in the number ofdays of treatment (± 1 day), rather than in the daily dose ofHHT or ara-C. For example, a patient who had achieved a lowestgranulocyte count greater than 2 x109/L and lowest platelet count greaterthan 100 x 109/L on a course of HHTand ara-C given for n days will receive the next course of HHT andara-C for (n + 1) days. In contrast, a patient who had achieved alowest granulocyte count of less than 109/Lor a lowest platelet count of less than 50 x109/L on a course given for n days willreceive the next course of HHT and ara-C for (n - 1)days.

Therapy was discontinued for the following reasons: (1)evidence of resistance with the optimal acceptable dose schedule, (2)disease transformation, (3) unacceptable toxicity (grade 3 to 4) afterdose reductions were made, (4) availability of other better options(eg, allogeneic SCT), or (5) patient or physician choice (eg, in thecase of a lack of cytogenetic response after 12 months of therapy). Iftoxicity was due to a particular agent (eg, hypotension or headachewith HHT), then the daily dose in subsequent courses was reduced by25% for grade 2 persistent toxicity and by 50% for grade 3 to 4toxicities. Toxicity was graded according to the National CancerInstitute common toxicity criteria.32

Criteriaand Statistical Considerations
Response criteria were as previously described.2,6 A CHR required a WBC countof less than 10 x 109/L withoutperipheral immature cells (blasts, promyelocytes, myelocytes), aplatelet count of 450 x 109/L orless, and disappearance of signs and symptoms of disease, includingpalpable splenomegaly. CHR was further classified by cytogeneticresponse based on best suppression of Ph-positive cells as follows:complete, Ph-positive 0%; partial, Ph-positive 1% to 34%; and minor,Ph-positive 35% to 90%. A major cytogenetic response included completeand partial cytogenetic responses (Ph-positive < 35%). A PHR wasdefined as for CHR, but with persistence of peripheral immature cellsand/or splenomegaly or thrombocytosis (but 50% or less ofpretreatment).

Results of {chi}2 tests arepresented as an indication of association of pretreatmentcharacteristics with cytogenetic response outcomes. Survival estimateswere based on the method of Kaplan and Meier33 and compared using the log-ranktest.34 For purposes ofcomparing results of this trial to those obtained on the trial thatimmediately preceded it,21patients were classified into risk groups on the basis of acombination of four factors (age, performance status, interval fromCML diagnosis to treatment, and percentage of peripheral basophils)previously reported as determinants of prognosis in late chronic-phaseCML.35


   RESULTS
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 ABSTRACT
 INTRODUCTION
 PATIENTSAND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Chronic-PhaseCML
One hundred patients had chronic-phase CML; 15 of them hadevidence of clonal evolution. All had evidence of active CML diseaseat the start of therapy (patients entered on therapy because ofcytogenetic resistance had IFN{alpha} therapy discontinued and wereexhibiting WBC or platelet count increases by the time HHT and ara-Ctherapy was started).

Among 85 patients with active chronic-phase disease butwithout clonal evolution, 61 (72%) achieved CHR, and 11 (13%) hadPHR. Cytogenetic response was noted in 26 patients (31%): major in 12(14%) and complete in four (5%) (Table 2).


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  		Table 2. Response to Therapy in 105 Patients Treated
 
Among 15 patients with evidence of clonal evolution, 11(73%) achieved CHR, three (20%) achieved a PHR, and one failed toachieve a response. A cytogenetic response was observed in six of the11 patients who had achieved CHR (55%; 40% of total); response wascomplete in one, partial in two, and minor in three patients. Clonalevolution disappeared in the patient achieving complete cytogeneticresponse and in two of three patients who had a minor cytogeneticresponse. One of the five patients who had CHR without Ph suppressionalso had complete suppression of the clonalevolution.

Accelerated-PhaseCML
Among five patients treated in accelerated-phase CML,three (60%) obtained CHR. One such patient achieved a completecytogenetic response.

SideEffects
Nonhematologic. Side effects of HHT and ara-C combination are listed inTable 3. Themost common side effects were diarrhea and headache during therapy,mostly attributable to HHT. They were rarely severe (two patients;2%). Other side effects such as skin rashes, nausea, vomiting,fatigue, and aches were unusual. Of note, hypotension and arrhythmiaswere observed in only 4% of patients.


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  		Table 3. Side Effects
 
Hematologic. With induction therapy, the incidence of granulocytopenialess than 0.5 x 109/L was 13% and theincidence of thrombocytopenia less than 30 x109/L was 4%. Significant anemia withhemoglobin less than 9.0 g/dL occurred in14% during induction and in50% of patients (14% of courses) during maintenancetherapy.

Prognosis byPretreatment Characteristics
Responses in chronic phase by different pretreatmentcharacteristics are listed in Table 4. No significantassociations were found between cytogenetic response and knownprognostic features. There were no differences in response by durationof chronic-phase disease or by prior exposure to ara-C. Survival wassignificantly worse among older patients. A trend for worse survivalwas also observed with thrombocytosis, increased marrow blasts, andlonger duration of chronic phase (Table 4).


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  		Table 4. Outcome Within Subsets Based on Pretreatment Characteristics
 
Follow-UpResults
The median number of HHT and ara-C courses was nine(range, one to 50 courses). The total number of courses received sofar was 1,071. With a median follow-up time of 25 months, 18 deathshave occurred, at times ranging from 5 to 39 months after the start oftherapy. The estimated survival rates at 2 and 4 years were 77% and55%, respectively (Fig1). The median time on therapy was 10 months(Fig 2). Atlast follow-up, 41 patients continued on therapy, and 64 were removedfrom study for reasons listed in Table 5.



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  		Fig1. Overall survival from start of

 


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  		Fig2. Time on

 

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  		Table 5. Patient Status (N = 105 Patients)
 
The course of patients who achieved a major cytogeneticresponse is listed in Table6. At the time of last follow-up, seven of the 16patients with cytogenetic response (44%) continued to have acytogenetic response: two were still in CHR on therapy, threedeveloped hematologic resistance, and four were removed from studybecause of toxicity (two patients), patient request (one patient), andcatheter-related problems (one patient). Two of 16 cytogeneticresponders died (one after allogeneic transplantation) compared with18 of 89 patients without a cytogenetic response.


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  		Table 6. Follow-Up of Patients With Major Cytogenetic Response
 
Comparisonof HHT Plus Ara-C to Previous HHT alone
To evaluate the possible impact on survival of addingara-C to HHT, we compared the results of the 100 patients in chronicphase for this trial with the previous trial of HHT alone, whichaccrued 73 patients with late chronic-phase CML. That trial wasconducted starting in 1989 and had identical eligibility requirementsto the HHT plus ara-C trial, except that there was no prior exposureto HHT or ara-C (not available then) and prior IFN{alpha} treatmentfailure was not required. Compared with the 100 patients in chronicphase receiving HHT plus ara-C, the patients treated with HHT alonewere younger (P = .07),but had a higher incidence of splenomegaly (P = .06) and leukocytosis(P = .002) and a higherincidence of peripheral blasts (P = .001) and clonal evolution(P = .03)(Table 7).


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  		Table 7. Comparison of HHT Versus HHT Plus Ara-C Study Group
 
Although there were differences in distributions ofpatient characteristics between the two trials (Table 7), a categorization ofpatients into risk groups based on four factors previously identifiedas important for prognosis in late chronic-phase CML35 suggested that patients on the twostudies had similar overall prognosis. A slightly higher proportion ofpatients receiving HHT alone fell in the lowest risk group, havingnone of the unfavorable factors (age >= 60 years, time fromdiagnosis to treatment >= 3 years, performance status of >= 1, orperipheral-blood basophils >= 7%). Response rates were nearlyidentical on the two trials (Table 7), but early resultssuggested that survival was somewhat prolonged for patients treatedwith HHT plus ara-C (Fig3; P= .04 [test stratified by risk group]). Similarresults were obtained with stratification by age and platelets(P = .03).



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  		Fig3. Survival with HHT with or without

 
We also analyzed all 173 patients in a multivariateanalysis to investigate possible associations of pretreatmentcharacteristics with survival, and we included therapy (HHT v HHT plus ara-C) as a prognosticvariable. The multivariate analysis selected older age (P = .01), splenomegaly (P < .01), and thrombocytosis(P = .02) asindependent poor significant factors, but therapy remained animportant prognostic factor (P= .026) favoring the addition ofara-C.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTSAND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The combination of HHT and ara-C in patients who hadexperienced treatment failure with IFN{alpha} yielded encouragingresults. Among patients treated in chronic phase, 72% achieved CHR;31% achieved a cytogenetic response, which was majorin14%. Considering that the study group included mostlyIFN{alpha}-resistant patients in late chronic phase who had fewtherapeutic options available, the median duration of disease controlof 10 months and estimated 4-year survival rate of 55% werefavorable. Our results suggest that HHT-based regimens may beeffective therapies for patients for whom IFN{alpha} therapy wasunsuccessful and who are not candidates for allogeneic SCT. They alsoindicate a potential role of HHT and ara-C as part of front-line CMLtherapy to improve the degree and duration of cytogenetic response andthe prognosis of patients with CML. Considering the acceptabletoxicity profile of the regimen, such investigational strategies maybe appropriate.

Comparable or even better results have also been reportedby Ernst et al,36 who usedHHT 2.5 mg/m2 daily and ara-C 7.5mg/m2 daily by continuous infusion for upto 14 days. In their report, the CHR rate among 44 patients treatedwas 93%, and cytogenetic responses were observed in 16 (44%) of 36patients treated for at least 6 months. Their study group included 14patients in early chronic-phase CML: all 14 (100%) achieved CHR, and11 (84%) of 13 assessable patients had a major cytogeneticresponse. It is not clear how much prior IFN{alpha} therapy thesepatients had received and whether they were clearly IFN{alpha}-resistantor had been entered onto the study because of unacceptableIFN{alpha}-related toxicities. The comparison of response rates withinsimilar patient subcategories would be of interest. Their studysuggested that even better CHR and cytogenetic response rates may beexpected depending on patient selection (eg, IFN{alpha} toxic patients,early chronic-phase CML), as had also been observed in our previousstudy of HHT (six courses followed by IFN{alpha} maintenance) in earlychronic-phase CML.22

An important question is the additional benefit of ara-Ccombined with HHT. Although we attempted to compare the twosequential studies at our institution (HHT alone in 73 patients withactive disease [21 of whom had clonal evolution] and thecurrent study with HHT plus ara-C), the comparison and evaluation ofthe benefit from addition of ara-C was difficult because ofdifferences in the study groups (Table 7), dose schedules, andfollow-up times. HHT alone was used for 10 to 14 days during remissioninduction and for 7 days every month during maintenancetherapy. Patients previously treated with HHT alone had been lessheavily pretreated with IFN{alpha} and had not been exposed to eitherHHT or to ara-C. However, it seems that the HHT plus ara-C combinationwas not associated with an increased risk of known or unpredictableside effects and may have improved outcome in CML after accounting forknown differences in prognostic factors within the two studygroups. The possible beneficial effect of ara-C on survival may bemediated through suppression of clones responsible for diseasetransformation.

Two issues, if resolved, may expand the potential use ofHHT in hematologic and perhaps solid tumors: (1) the route-scheduledelivery, and (2) the mechanisms underlying the cardiovascular sideeffects with shorter infusion schedules. The continuous-infusionschedule, although effective against CML, is cumbersome and limits theinvestigation of even lower-dose longer-exposure schedules (eg, 0.5 to1 mg/m2 for 3 to 4 weeks). A safesubcutaneous schedule may allow reinvestigating HHT, not only in CML,but also as maintenance therapy in AML, as differentiation therapy inAPL, and as a chronic subcutaneous low-dose schedule in MDS. All ofthese are diseases in which HHT investigations had been discouragedbecause of the HHT toxicity profile, despite evidence ofefficacy.17-20,37 Understanding the etiology of thecardiovascular problems may allow a targeted development of a newgeneration of HHT derivatives designed to avoid cardiovascular sideeffects and to expand the spectrum of antitumor activity (as has beenshown for deoxynucleoside cytidine analogs, eg, ara-C v gemcitabine). This will thenrejuvenate anticancer research with HHT-like molecules.

HHT has shown activity in hematologic cancers other thanCML and AML that needs further exploration. Low-dose harringtonine wasreported to induce remissions in APL.37 Ten patients with APL receivedharringtonine 1 to 3 mg over 4 to 5 hours daily until completeresponse; seven (70%) achieved complete response after a median of 71days and a median cumulative dose of 136 mg. HHT has already shown invitro effects on apoptosis and differentiation,26,27,38 which mayprove helpful not only against APL but also against other cancerswhere maturation arrest is pathophysiologic, such as MDS. Among 15patients with MDS treated by Feldman et al,19 four (27%) achieved objectiveresponses. Myelosuppressive complications were significant at the doseschedule used (5 mg/m2 by continuousinfusion daily for 9 days), and a high mortality rate precludedfurther investigations with this schedule.19 Lower dose schedules of HHT, as inCML, may prove effective and less toxic in theseconditions.

Recent studies have reported encouraging results with anew BCR-ABL tyrosine kinaseinhibitor, STI-571. Among patients treated in chronic-phase CML whohad experienced treatment failure with IFN{alpha} (because of resistanceor toxicity), the CHR rate was 100% when STI-571 was given at 300 mgor more orally daily; cytogenetic responses were alsoobserved. STI-571 was also beneficial in the treatment ofaccelerated-blastic phases of CML.39,40 Future studies will better define therelative benefits of STI-571 and HHT plus ara-C, alone or incombinations, in patients who have been treated unsuccessfully withIFN{alpha}.

In summary, the combination of HHT and low-dose ara-C wassafe and effective in the dose schedule used in our study in patientswith late chronic-phase CML. This now offers such patients (ifIFN{alpha} treatment had failed) a good treatment option and indicatesthat further studies with IFN{alpha} in front-line CML therapy arewarranted.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTSAND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. KantarjianHM, O’Brien S, AnderliniP, et al:Treatment of myelogenous leukemia: Current status and investigationaloptions. Blood 87:3069-3081, 1996[Free Full Text]

2. KantarjianHM, Giles FJ, O’BrienSM, et al:Clinical course and therapy of chronic myelogenous leukemiawith interferon-alpha and chemotherapy. Hematol Oncol Clin North Am 12:31-80, 1998[Medline]

3. GoldmanJM, Szydlo R, HorowitzMM, et al:Choice of pre-transplant treatment and timing oftransplants for chronic myelogenous leukemia in chronicphase. Blood 82:2235-2238, 1993[Abstract/Free Full Text]

4. GratwohlA, Hermans J, NiederwieserD, et al:Bone marrow transplantation for chronic myeloid leukemia: Long-term results—Chronic LeukemiaWorking Party of the European Group for Bone MarrowTransplantation. Bone MarrowTransplant 12:509-516, 1993[Medline]

5. HehlmannR, Ansari H, Hasford, et al:Comparative analysis of the impact of risk profile and ofdrug therapy on survival in CML using Sokal’s index and a newscore: German Chronic Myeloid Leukaemia(CML) Study Group. Br J Haematol 97:76-85, 1997[Medline]

6. KantarjianHM, Smith TL, O’BrienS, et al:Prolonged survival in chronic myelogenous leukemia aftercytogenetic response to interferon-alpha therapy. Ann Intern Med 122:254-261, 1995[Abstract/Free Full Text]

7. GuilhotF, Chastang C, MichalletM, et al:Interferon alfa-2b combined with cytarabine versusinterferon alone in chronic myelogenous leukemia: French Chronic Myeloid Leukemia StudyGroup. N Engl J Med 337:223-229, 1997[Abstract/Free Full Text]

8. TuraS: Cytarabine increases karyotypic response in alpha-IFNtreated chronic myeloid leukemia patients: Results of a national prospective randomized trial. Blood 92: 317, 1998 (abstr)

9. KantarjianHM, O’Brien S, SmithT, et al:Treatment of Philadelphia chromosome-positive early chronicphase chronic myelogenous leukemia with daily doses of interferonalpha and low-dose cytarabine. J ClinOncol 17:284-292, 1999[Abstract/Free Full Text]

10. The Italian Cooperative StudyGroup on Chronic Myeloid Leukemia :Interferon alfa-2a as compared with conventional chemotherapy for thetreatment of chronic myeloid leukemia. N Engl J Med, 330:820-825, 1994

11. AllanNC, Richards SM, ShepherdPC: UKMedical Research Council randomized, multicenter trial ofinterferon-alpha n1 for chronic myeloid leukaemia: Improved survival irrespective of cytogeneticresponse—The UK Medical Research Council’s Working Partiesfor Therapeutic Trials in Adult Leukemia. Lancet 345:1392-1397, 1995[Medline]

12. Chronic Myeloid LeukemiaTrialists’ Collaborative Group :Interferon alfa versus chemotherapy for chronic myeloid leukemia: Ameta-analysis of seven randomized trials. J Natl Cancer Inst, 89:1616-1620, 1997

13. Cephalotaxus ResearchCoordinating Group: Cephalotaxine esters inthe treatment of acute leukemia: Apreliminary clinical assessment. Chin Med J 2:263-272, 1976[Medline]

14. Chinese People’s Liberation Army 18thHospital: On the treatment of leukemias: Clinical analysis of 72cases. Zhonghua Yizue Zazhi, 58:163, 1978(abstr)

15. LeghaSS, Keating M, PicketS, et al:Phase I clinical investigation of homoharringtonine. Cancer Treat Rep 68:1085-1091, 1984[Medline]

16. NeidhartJA, Young DC, KrautE, et al:Phase I trial of homoharringtonine administered byprolonged continuous infusion. CancerRes 46:967-969, 1986[Abstract/Free Full Text]

17. WarrellRP Jr, Coonley CJ, GeeTS: Homoharringtonine: An effectivenew drug for remission induction in refractory non-lymphoblasticleukemia. J Clin Oncol 3:617-621, 1985[Abstract]

18. FeldmanE, Arlin Z, AhmedT, et al:Homoharringtonine is safe and effective for patients withacute myelogenous leukemia (I). Leukemia 6:1185-1188, 1992[Medline]

19. FeldmanEJ, Seiter KP, AhmedT, et al:Homoharringtonine in patients with myelodysplastic syndrome(MDS) and MDS evolving to acute myeloid leukemia. Leukemia 10:40-42, 1996[Medline]

20. KantarjianH, Keating M, McCredieK, et al:Phase II study of homoharringtonine in refractory acutemyelogenous leukemia. Cancer 63:813-817, 1989[Medline]

21. O’BrienS, Kantarjian H, KeatingM, et al:Homoharringtonine therapy induces responses in patientswith chronic myelogenous leukemia in late chronic phase. Blood 86:3322-3326, 1995[Abstract/Free Full Text]

22. O’BrienS, Kantarjian H, KollerC, et al:Sequential homoharringtonine and interferon-alpha in thetreatment of early chronic phase chronic myelogenousleukemia. Blood 93:4149-4153, 1999[Abstract/Free Full Text]

23. SokalJ, Beingner SH: Low-dose cytosine arabinoside bysubcutaneous infusion in early and advanced chronic granulocyticleukemia. Blood 68: 233a, 1986 (abstr)

24. RobertsonMJ, Tantravahi R, GriffinJD, et al:Hematologic remission and cytogenetic improvement aftertreatment of stable-phase chronic myelogenous leukemia with continuousinfusion of low-dose cytarabine. Am JHematol 43:95-102, 1993[Medline]

25. KantarjianH, Keating M, EsteyE, et al:Treatment of advanced Philadelphia chromosome-positivechronic myelogenous leukemia with interferon-alpha and low-dosecytarabine. J Clin Oncol 10:772-778, 1992[Abstract/Free Full Text]

26. VisaniG, Russo D, OttavianiE, et al:Effects of homoharringtonine alone and in combination withalpha interferon and cytosine arabinoside on in vitro growth andinduction of apoptosis in chronic myeloid leukemia and normalhematopoietic progenitors. Leukemia 11:624-628, 1997[Medline]

27. O’BrienS, Keating A, KantarjianH, et al:Homoharringtonine induces apoptosis in chronic myelogenousleukemia cells. Blood 82:555a, 1993 (abstr, suppl 1)

28. SokalJ, Leong SS, GomezGA: Preferential inhibition by cytarabine of CFU-GM frompatients with chronic granulocytic leukemia. Cancer 59:197-202, 1987[Medline]

29. KantarjianHM, Dixon D, KeatingMJ, et al:Characteristics of accelerated disease in chronicmyelogenous leukemia. Cancer 61:1441-1446, 1988[Medline]

30. MajlisA, Smith TL, TalpazM, et al:Significance of cytogenetic clonal evolution in chronicmyelogenous leukemia. J Clin Oncol 14:196-203, 1996[Abstract]

31. CortesJ, Talpaz M, O’BrienS, et al:Suppression of cytogenetic clonal evolution with interferonalfa therapy in patients with Philadelphia chromosome-positive chronicmyelogenous leukemia. J Clin Oncol 16:3279-3285, 1998[Abstract]

32. National CancerInstitute : Guidelines for reporting ofadverse drug reactions. Bethesda, MD, Division of Cancer Treatment, National CancerInstitute, 1988

33. KaplanEL, Meier P: Nonparametric estimation fromincomplete observation. J Am StatAssoc 58:457-481, 1958

34. MantelN: Evaluation of survival data and two new rank orderstatistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

35. RodriguezJ, Cortes J, SmithTL, et al:Determinants of prognosis in late chronic-phase chronicmyelogenous leukemia. J Clin Oncol 16:3782-3787, 1998[Abstract/Free Full Text]

36. ErnstTJ, Vance E, AlyeaE III, et al:Homoharringtonine and low-dose Ara-C is a highly effectivecombination for the treatment of CML in chronic phase. Blood 90: 517a, 1997 (abstr, suppl1)

37. Jing-SongY, Xiao-Hong W, Guang-HuiF, et al:Small dose harringtonine induces complete remission inpatients with acute promyelocytic leukemia. Leukemia 2:427-429, 1988[Medline]

38. BoydAW, Sullivan JR: Leukemic cell differentiation invivo and in vitro: Arrest of proliferationparallels the differentiation induced by the antileukemic drugharringtonine. Blood 6:384-392, 1984

39. DrukerBJ, Talpaz M, RestaD, et al:Clinical efficacy and safety of an ABL specific tyrosinekinase inhibitor as targeted therapy for chronic myelogenous leukemia. Blood 94: 368a, 1999 (abstr, suppl1)

40. DrukerBJ, Kantarjian H, SawyersCL, et al:Activity of an ABL specific tyrosine kinase inhibitor inpatients with BCR-ABL positive acute leukemias, including chronicmyelogenous leukemia in blast crisis. Blood 94: 697a, 1999 (abstr, suppl1)

Submitted January 24, 2000; accepted June 6, 2000.


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