Seven Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients in first complete remission received maintenance therapy with imatinib alone. Two-year progression-free survival was 75%. Quantitative polymerase-chain-reaction (qPCR) monitoring of BCR-ABL showed that: (i) persisting molecular complete response (CR) was associated with long-lasting CR; (ii) molecular relapse did not invariably mean hematologic relapse; (iii) only the wide and rapid increment of BCR-ABL values was predictive of leukemia relapse

LUPPI, Mario

MARASCA, Roberto

MARTINELLI, Silvia

POTENZA, Leonardo

RIVA, Giovanni

TORELLI, Giuseppe

English

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

Letters to the Editorhaematologica/the hematology journal | 2005; 90(9) | 1275 |Chronic Myeloid LeukemiaEfficacy of imatinib mesylate as maintenancetherapy in adults with acute lymphoblasticleukemia in first complete remissionSeven Philadelphia chromosome-positive acutelymphoblastic leukemia (Ph+ALL) patients in firstcomplete remission received maintenance therapywith imatinib alone. Two-year progression-freesurvival was 75%. Quantitative polymerase-chain-reaction (qPCR) monitoring of BCR-ABL showedthat: (i) persisting molecular complete response(CR) was associated with long-lasting CR; (ii)molecular relapse did not invariably mean hemato-logic relapse; (iii) only the wide and rapid incre-ment of BCR-ABL values was predictive ofleukemia relapse. haematologica 2005; 90:1275-1277(http://www.haematologica.org/journal/2005/9/1275.html)Imatinib mesylate has been shown to induce remis-sions in more than two-thirds of patients withrelapsed/refractory Philadelphia chromosome positiveacute lymphoblastic leukemia (Ph+ALL), although forshort time. Serial quantitative reverse-transcriptase poly-merase-chain-reaction (qRT-PCR) monitoring of BCR-ABL has shown utility in predicting leukemia relapse andbridging the time to bone marrow transplantation(BMT).1-5 We evaluated the efficacy of imatinib alone forlong-term maintenance therapy in seven consecutivePh+ALL patients in first hematologic complete remission(hCR), and the usefulness of a strict minimal residual dis-ease (MRD) follow-up to identify patients who may ben-efit from prolonged imatinib maintenance. Table 1A summarizes the clinical characteristics of theseven patients. At diagnosis, karyotypic analysis showedthe t(9;22) translocation in all patients, and revealed addi-tional chromosomal alterations in three (43%) out of theseven patients, namely +14, del(10q) and del(20). In fivepatients induction treatment was a multiagent chemother-apy regimen, detailed in Table 1A. The other two patients,older than 65 years, received prednisone 40 mg/m2 dailyand imatinib 800 mg/day for 30 days as induction treat-ment. At the end of induction, all patients were in com-plete remission (CR) and received maintenance treatmentwith imatinib 800 mg/day until toxicity or leukemiarelapse (Table 1A). MRD monitoring was performed onbone marrow aspirates collected at admission, at the endof induction treatment and then, monthly, during themaintenance therapy. Molecular CR (mCR) was defined asdescribed by Gabert et al.6 The definition of hCR and thealgorithms for MRD evaluation were drawn fromScheuring et al.3 and were modified as follows: minimumBCR-ABL level: the lowest measured relative BCR-ABLlevel prior to an increase or identical value; increased BCR-ABL level: the highest value after the minimum (it was con-sidered if the sample was obtained at least 15 days prior tohematologic relapse [hRel]; magnitude of increase: the logratio between the increased BCR-ABL and the minimum, asdefined above; persisting mCR: mCR sustained for at leastthree months and short mCR: mCR detected in a singleobservation or sustained for less than three months.Kaplan-Meier curves and the hazard rate were calculatedusing STATA (release 8) software. Overall survival (OS)and progression-free survival (PFS) are shown in Figures1A and B. The hazard rate was 0.00021617. Six out ofseven patients (86%) were still in hCR at a median follow-Table 1 A. Characteristics of patients at baseline and their treat-ment outcome.Characteristics PatientsMedian age, y (range) 59 (34-79)Sex, no (%)Male 3 (43)Female 4 (57)Subtype of ALL, no. (%)c-ALL 5 (72)Pre-B-ALL 1(14)Pro-B-ALL 1(14)p190Bcr-Abl vs p210Bcr-Abl, no. (%)m-Bcr-Abl 4 (57)M- Bcr-Abl 3 (43)Karyotype, no. (%)Additional cytogenetics abnormalities 3 (43)t(9;22) 7 (100)CNS leukemia, no. (%) 0 (0%)Induction chemotherapy regimen, no. (%)DNM+VCR+ PDN for 30 days 5 (71)PDN 40 mg+Imatinib 800 mg/day for 30 days 2*(29)Outcome of InductionhCR 7 (100)Consolidation/maintenance regimen, no. (%)Imatinib 800 mg/day 7 (100%)CNS Prophylaxisduring induction and maintenanceMTX i.t. 15 mg/monthly for 16 months 7 (100%)DNM: daunorubicin; PDN: prednisone; VCR: vincristine; MTX: methotrexate;hCR: hematologic complete remission. *Two patients over 65 years old.Table 1B. BCR-ABL/β2microglobulin after best MRD value and itsrelation to relapse.BCR-ABL level Number of patients Number of relapses (%)> 10-4 2 1 (50)< 10-4 2 0Table 1C. Adverse events during imatinib treatment.Toxicity Grade I or II, no. (%) Grade III or IV, no. (%)Nausea/vomiting 6 (86) 1 (14)Periorbital edema 7 (100) −Cutaneous rash 1 (14) −Weakness 5 (71) −Anemia 2 (28) −Neutropenia 4 (57) 3 (43)Thrombocytopenia 4 (57) 3 (43)| 1276 | haematologica/the hematology journal | 2005; 90(9)Letters to the Editorup of 729 days (range 364.8 to 1003.2 days). Only one(14%) patient, who had been treated with the chemother-apy induction regimen, relapsed 456 days and died 729days after the start of imatinib. The median BCR-ABLvalue after four weeks of imatinib was 4.1×10-4 (range 1×10-5- 4.5×10-3). All the patients achieved mCR at least once.Four out of the seven patients (57%) are still in mCR. ThemCR persisted for a median of 182.4 days (range 91.2-638.4 days). All of the five patients with persisting mCRare still in CR as is one of the two patients with shortmCR. At a median of 319.2 days (range 91.2 to 364.8 days)from molecular relapse (mRel), three (75%) out of fourpatients maintained the hCR (Figure 1C). An increase ofMRD were observed in four (67%) of the seven patients.The magnitude of increase is shown in Figure 1D. TheBCR-ABL/β2microglobulin ratio after the best MRD valueand its relation to relapse are shown in Table 1B. Adverseevents are shown in Table 1C. In accordance with previousreports of low hepatic toxicity of imatinib treatment,4,7none of our patients developed liver function abnormali-ties during imatinib maintenance. Of note, only onepatient had presented severe hepatic toxicity (WHO gradeIV), on day +20 of the induction chemotherapy, which waswithdrawn.This is the first reported homogenous series in whichimatinib alone was used successfully as maintenance treat-ment. Our data show 2-year OS and PFS higher than thosereported in the literature for Ph+ALL patients treated witheither chemotherapy, or allogeneic BMT, or imatinib as sal-vage treatment (75% versus 15%, 64% and 22%, respec-tively).1-5,7-9 In agreement with the literature data,3,4,8 weobserved: (i) a longer period of mCR in long-term respon-ders, with BCR-ABL levels either lower than the 10-2threshold after four weeks of imatinib, or lower than 10-4after the best MRD value; (ii) a rapid increase of BCR-ABLlevel of more than 2 log in the only patient who relapsed.Because of the limited sample size and low relapse rate, wecould not identify a threshold predictive of good responseor of imminent relapse. Similarly, we could not correlate the additional cytoge-netic abnormalities with the clinical outcome of thepatients. In contrast with previously reported data,3,10 mRelwas not invariably associated with hRel in our patients,probably, due either to the different disease status of thepatients (first CR versus relapsed/refractory), or to themechanism of action of imatinib, more specific than thegraft-versus-leukemia effect, at least in some cases, or tothe higher dose of imatinib administered (800 mg vs 600mg/daily). Recently, a dose increase of imatinib has beendemonstrated to induce higher rates of major cytogeneticremission and mCR in chronic myeloied leukemia,11 and torestore the mCR state in Ph+ALL patients who have had amolecular relapse either after allogeneic BMT or duringimatinib as salvage treatment.12,13Issues that need to be addressed include the optimalduration of treatment, whether imatinib may replace orsupport chemotherapy and whether such strict MRD mon-itoring may help to identify which patients could delay oravoid BMT, especially in the case of unavailability of a sib-ling donor.Leonardo Potenza, Mario Luppi, Giovanni Riva,Roberto Marasca, Silvia Martinelli, Giuseppe TorelliSection of Haematology, Department of Oncology and Hematology,University of Modena and Reggio Emilia,Modena, ItalyKey words: imatinib, Ph+ALL, MRD, consolidation/maintenancetherapy.Correspondence: Mario Luppi M.D., Ph.D., Department ofOncology and Haematology. Section of Haematology, Universityof Modena and Reggio Emilia, Modena, Italy. Phone: international+39.059.4224641. Fax: international +39.059.4224549.E-mail: mluppi@unimore.itReferences1. Radich JP. Philadelphia chromosome-positive acute lympho-cytic leukemia. Hemato Oncol Clin North Am 2001;15:21-36.2. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, FordJM, et al. Activity of a specific inhibitor of the BCR-ABL tyro-sine kinase in the blast crisis of chronic myeloid leukemia andacute lymphoblastic leukemia with the Philadelphia chromo-some. N Engl J Med 2001;344:1038-42.3. Scheuring UJ, Pfeifer H, Wassmann B, Bruck P, Gehrke B,Petershofen EK, et al. Serial minimal residual disease (MRD)analysis as a predictor of response duration in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) during ima-tinib treatment. Leukemia 2003;17:1700-6.4. Wassmann B, Pfeifer H, Scheuring UJ, Binckebanck A,Goekbuget N, Atta J, et al. Early prediction of response inFigure 1. A-B. Response to imatinib maintenance by Kaplan-Meieranalysis. Overall survival and progression-free survival calculatedfrom the start of maintenance with imatinib for all seven patients.C. MRD follow-up. MRD monitoring of all seven patients monitoredfrom 4 weeks after the start of imatinib. The median follow-up is729.4 days; (range 364.8-1003.2 days). 1×10-5 represents thenegative threshold of the RT-PCR technique used. D. Magnitude ofBCR-ABL/β2 microglobulin increase. At the time of evaluating ofBCR-ABL/β2 microglobulin increase, all the patients had a nega-tive BCR-ABL value as minimum BCR-ABL level. Patient 3relapsed, showing an increase of 3.3 log. The median increase inthe other three patients was 0.63 log (0.63 log, 0.58 log and 1.18log). The remaining three patients did not have a BCR-ABLincrease and are still in mCR.A BMRD amountLeukemia relapseOverall survivalSurvival rateSurvival rateProgression-free survivalTime (months)BM minRatio BCR/AB/ββ 2m××100Ratio BCR/AB/ββ 2m××1001,00E+001,00E-011,00E-021,00E-031,00E-041,00E-051,00E+001,00E-011,00E-021,00E-031,00E-041,00E-05Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7NegativeBM incrNegative tresholdCD♦♦××0 6 12 18 24 30 36Time (months)0 6 12 18 24 30 36Time (months)0.000.250.500.751.000.000.250.500.751.000 3 6 9 12 15 18 21 24 27 30 33Letters to the Editorhaematologica/the hematology journal | 2005; 90(9) | 1277 |patients with relapsed or refractory Philadelphia chromo-some-positive acute lymphoblastic leukemia (Ph+ ALL) treat-ed with imatinib. Blood 2004103:1495-8.5. Lee S, Kim DW, Kim YJ, Chung NG, Kim YL, Hwang JY, et al.Minimal residual disease-based role of imatinib as a first-lineinterim therapy prior to allogeneic stem cell transplantation inPhiladelphia chromosome-positive acute lymphoblasticleukemia. Blood 2003;102:3068-70.6. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D,Pallisgaard N, et al. Standardization and quality control stud-ies of 'real-time' quantitative reverse transcriptase polymerasechain reaction of fusion gene transcripts for residual diseasedetection in leukemia - a Europe Against Cancer program.Leukemia 2003;17:2318-57.7. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, ReiffersJ, Silver RT, et al. A phase 2 study of imatinib in patients withrelapsed or refractory Philadelphia chromosome-positiveacute lymphoid leukemias. Blood 2002;100:1965-71.8. Towatari M, Yanada M, Usui N, Takeuchi J, Sugiura I, Take-uchi M, et al. Combination of intensive chemotherapy andimatinib can rapidly induce high-quality complete remissionfor a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Japan Adult LeukemiaStudy Group. Blood 2004;104:3507-12.9. Piccaluga PP, Malagola M, Amabile M, Rondoni M, Paolini S,Pane F, et al. The achievement of molecular complete remis-sion during treatment with imatinib mesylate correlates withrelapse-free survival in bcr/abl-positive acute lymphoidleukemia patients. Haematologica 2004;89:1269-70.10. Mitterbauer G, Fodinger M, Scherrer R, Knobl P, Jager U,Laczika K, Schwarzinger I, Gaiger A, Geissler K, Greinix H.PCR-monitoring of minimal residual leukaemia after conven-tional chemotherapy and bone marrow transplantation inBCR-ABL-positive acute lymphoblastic leukaemia. Br JHaematol 1995;89:937-41.11. Kantarjian H, Talpaz M, O'Brien S, Garcia-Manero G,Verstovsek S, Giles F, et al. High-dose imatinib mesylate ther-apy in newly diagnosed Philadelphia chromosome-positivechronic phase chronic myeloid leukemia. Blood 2004; 103:2873-8.12. Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G,Scheuring UJ, et al. Early molecular response to post-trans-plant imatinib determines outcome in MRD-positive Philadel-phia-positive acute lymphoblastic leukemia (Ph+ALL). Blood2005;106:458-63.13. Piccaluga PP, Malagola M, Rondoni M, Amabile M, Paolini S,Soverini S, et al. Dose increase of imatinib mesylate may over-come acquired resistance in bcr/abl-positive acute lymphoidleukemia. Eur J Haematol 2004; 72:302-3.

Efficacy of imatinib mesylate as maintenance therapy in adults with acute lymphoblastic leukemia in first complete remission

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Efficacy of imatinib mesylate as maintenance therapy in adults with acute lymphoblastic leukemia in first complete remission

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