Bone Marrow Transplants from HLA-Identical Siblings as Compared with Chemotherapy for Children with Acute Lymphoblastic Leukemia in a Second Remission
A. John Barrett, Mary M. Horowitz, Brad H. Pollock, Mei-Jie Zhang, Mortimer M. Bortin, George R. Buchanan, Bruce M. Camitta, Judith Ochs, John Graham-Pole, Philip A. Rowlings, Alfred A. Rimm, John P. Klein, Jonathan J. Shuster, Kathleen A. Sobocinski, and Robert Peter Gale
Background It is unclear how best to treat children with acutelymphoblastic leukemia who are in a second remission after abone marrow relapse. For those with HLA-identical siblings,the question of whether to perform a bone marrow transplantationor to continue chemotherapy has not been answered.
Methods We compared the results of treatment with marrow transplantsfrom HLA-identical siblings in 376 children, as reported tothe International Bone Marrow Transplant Registry, with theresults of chemotherapy in 540 children treated by the PediatricOncology Group. A preliminary analysis identified variablesassociated with treatment failure in both groups. We selectedcohorts by matching these variables. A possible bias associatedwith differences in the interval between remission and treatmentwas controlled for by choosing matched pairs in which the durationof the second remission in the chemotherapy recipient was atleast as long as the time between the second remission and transplantationin the transplant recipient. A total of 255 matched pairs werestudied.
Results The mean (±SE) probability of a relapse at fiveyears was significantly lower among the transplant recipientsthan among the chemotherapy recipients (45 ±4 percentvs. 80 ±3 percent, P<0.001). At five years the probabilityof leukemia-free survival was higher after transplantation thanafter chemotherapy (40 ±3 percent vs. 17 ±3 percent,P<0.001). The relative benefit of transplantation as comparedwith chemotherapy was similar in children with prognostic factorsindicating a high or low risk of relapse (the duration of thefirst remission, age, leukocyte count at the time of the diagnosis,and phenotype of the leukemic cells).
Conclusions For children with acute lymphoblastic leukemia ina second remission, bone marrow transplants from HLA-identicalsiblings result in fewer relapses and longer leukemia-free survivalthan does chemotherapy.
Current regimens of intensive chemotherapy produce remissionsin almost all children with acute lymphoblastic leukemia. Additionaltreatment with consolidation and maintenance chemotherapy curesup to 70 percent of these children, but in about 25 percentof them the disease recurs in the bone marrow1,2,3. Most ofthese children have a second remission with chemotherapy, butthe choice of subsequent treatment is controversial. One approachis more chemotherapy. In large published studies, chemotherapyresulted in leukemia-free survival at five years in 8 to 76percent of patients but generally in 10 to 20 percent4,5,6,7,8,9,10,11.The main determinant of the outcome of chemotherapy is the durationof the first remission: a child with a brief first remissionfares worse than one with a long first remission. Other variablesreported to predict the outcome of chemotherapy are age, theleukocyte count at the time of the diagnosis, and the phenotypeof the leukemic cells. Resistance to chemotherapy is the maincause of treatment failure.
Bone marrow transplantation from an HLA-identical sibling isan alternative treatment for children in a second remission12,13,14,15,16.Transplantation has resulted in leukemia-free survival at fiveyears in 22 to 64 percent of patients in large series17,18,19,20,21,22,23,24.The duration of the first remission is also a primary determinantof the outcome of bone marrow transplantation19,20,21. Unlikethe results with chemotherapy, treatment-related mortality andresistant leukemic cells contribute equally to the failure oftreatment with bone marrow allografts.
Whether a child with acute lymphoblastic leukemia in a secondremission who has an HLA-identical sibling should receive chemotherapyor a bone marrow transplant is a matter of intense debate15,16,24,25.To our knowledge, no randomized trials have addressed this question,because the relatively low incidence of acute lymphoblasticleukemia and the limited number of HLA-matched donors make accrualof patients difficult, even for multicenter cooperative groups26.Other reports comparing chemotherapy and transplantation areeither inconclusive or contradictory15,22,25,26,27,28. In aprevious comparison of data from the International Bone MarrowTransplant Registry (IBMTR) and data from trials with chemotherapy,we suggested that bone marrow transplantation in patients ina second remission after a bone marrow relapse resulted in ahigher probability of leukemia-free survival in children witha short first remission ( 18 months) but not in those with along first remission29. However, prognostic and treatment informationthat might have accounted for the difference was not availablefor the patients receiving chemotherapy.
In this study we performed a matched-pair analysis to comparethe results of treatment with bone marrow transplants from HLA-identicalsiblings in 255 children, as reported to the IBMTR, with theresults of chemotherapy in 255 similar children enrolled intrials conducted by the Pediatric Oncology Group.
Methods
Patients Treated with Transplantation
The IBMTR collects data from over 250 transplantation centersworldwide that report information on consecutive patients receivingallogeneic or identical-twin bone marrow transplants. Participantsaccount for about two thirds of all active transplantation teams30.The registry, which includes information on 40 to 50 percentof all allogeneic bone marrow transplantations since 1970, isthe largest data base for transplantations in patients withacute lymphoblastic leukemia. For this study, the cohort oftransplant recipients was drawn from a population of patients18 years of age or younger who received transplants from HLA-identicalsiblings between 1983 and 1991, while they were in a secondremission after a bone marrow relapse. Children with an isolatedextramedullary relapse, lymphoma with a leukemic transformation,or Down's syndrome were excluded. The selection of candidatesfor transplantation varied according to the policies of thetransplantation teams. Most transplantations were performedin children without serious concurrent illnesses. The intervalbetween the second remission and transplantation varied from1 to 222 weeks (median, 10). For this patient population, theresults of transplantation reported to the IBMTR are similarto those reported by most centers12,13.
Patients Treated with Chemotherapy
The Pediatric Oncology Group is a multicenter clinical-trialsgroup including over 80 institutions in the United States, Canada,and Europe. The cohort of patients with acute lymphoblasticleukemia who were treated with chemotherapy was drawn from apopulation of patients who were 18 years of age or younger andhad had a second remission after treatment for a first bonemarrow relapse. They were treated between April 1983 and May1991 in study 8303, 8304, 8710, or 8862. Details of the treatmentsare reported elsewhere11,31 and are also available from thegroup's statistical center. Study 8303 excluded patients whohad a relapse more than six months after maintenance chemotherapyhad been discontinued (late relapse). Study 8304 included onlypatients with a late relapse. Study 8710 included patients witheither an early or a late relapse but excluded those with T-cellacute lymphoblastic leukemia or Down's syndrome. Study 8862included patients with T-cell acute lymphoblastic leukemia orT-cell non-Hodgkin's lymphoma but excluded those with Down'ssyndrome. The patients with T-cell non-Hodgkin's lymphoma wereexcluded from this analysis. The results of these trials aretypical of the published results of studies in the United Statesand other countries in which children with acute lymphoblasticleukemia are treated after a first bone marrow relapse1,2,3.
Statistical Analysis
The initial study group consisted of 376 children in the IBMTRcohort and 540 in the Pediatric Oncology Group cohort. Two potentialsources of bias were considered in comparing these groups. First,patient- and disease-related variables associated with the outcomeof chemotherapy might have influenced the selection of patientsfor bone marrow transplantation. This could have resulted inan imbalance in prognostic factors between the groups. Second,the IBMTR cohort included only children who were in remissionlong enough to receive a transplant, whereas the Pediatric OncologyGroup cohort included all children enrolled in the group's studieswho had a second remission. The transplantation group thereforeexcluded children who died early or had an early second relapse.This could have introduced a bias favoring transplantation32,33.
We used the following statistical methods to address these issues.First, using a Cox proportional-hazards regression,34 we identifiedpatient- and disease-related variables associated with treatmentfailure (relapse or death) in each group. The variables we testedin the model were age, sex, the leukocyte count at the timeof the diagnosis, the phenotype, the year of the diagnosis,and the duration of the first remission. We then selected pairsof chemotherapy and transplant recipients by matching membersfrom the two cohorts for all variables associated with the outcomeof either therapy (P 0.1). These variables were the age atthe time of the second remission (0 to 2, 3 to 10, or 11 to18 years), the leukocyte count at the time of the diagnosis( 50,000, 50,001 to 100,000, or >100,000 cells per cubicmillimeter), the T-cell phenotype (yes or no), and the durationof the first remission (within six months). If more than onepatient in the chemotherapy group was eligible for matchingwith a patient in the transplantation group, we selected thechemotherapy recipient with a first remission closest in durationto that of the transplant recipient. In addition, the chemotherapyrecipient in each pair was selected from among the childrenwith a second remission at least as long as the interval betweenthe second remission and transplantation for the transplantrecipient. We identified 255 pairs who met these criteria.
The primary end points we analyzed were the duration of survivalwithout a relapse of leukemia (leukemia-free survival), thetime to treatment-related mortality (death in continuous completeremission), and the time to a relapse. The probabilities ofleukemia-free survival, treatment-related mortality, and relapsewere calculated with Kaplan-Meier methods and compared by pairedlog-rank test35. For the analyses of leukemia-free survival,treatment was considered to have failed at the time of a relapseat any site or at the time of death from any cause; data onpatients who were alive and in continuous complete remissionwere censored only at the time of the last follow-up visit.For analyses of treatment-related mortality, failure was definedas death during a continuous complete remission; data were censoredat the time of a relapse or, among patients with continuousremissions, at the time of the last follow-up visit. For analysesof relapse, failure was defined as the recurrence of acute lymphoblasticleukemia at any site; data were censored at the time of a deathor the last follow-up visit during a continuous remission. Weused a Cox proportional-hazards regression model to test forinteractions between treatment and age, sex, the leukocyte countat the time of the diagnosis, the leukemia-cell phenotype, andthe duration of the first remission.
Results
Characteristics of the Patients
Table 1 shows the variables associated with treatment failurein the unmatched groups of children with acute lymphoblasticleukemia in a second remission who received either chemotherapyor bone marrow transplants. Among the 540 patients who receivedchemotherapy, an increased risk of treatment failure was associatedwith a leukocyte count >100,000 per cubic millimeter at thetime of the diagnosis and by a first remission that was 36months long. Among the 376 children who received marrow transplants,an increased risk of treatment failure was associated with anage >10 years, the presence of a T-cell phenotype, and afirst remission lasting 36 months. Table 2 shows the characteristicsof the matched cohorts, which were very similar.
Table 1. Variables Significantly Associated with Treatment Failure (Relapse or Death) among Children with Acute Lymphoblastic Leukemia in a Second Remission Receiving either Continued Chemotherapy or Bone Marrow Transplants from HLA-Identical Siblings.
Table 2. Characteristics of the Matched Chemotherapy and Transplantation Cohorts.
Outcome
Figure 1 shows the actuarial probabilities of leukemia-freesurvival in the unmatched transplantation and chemotherapy cohorts.The mean (±SE) probability of leukemia-free survivalat five years was 36 ±3 percent in the transplantationgroup and 16 ±2 percent in the chemotherapy group (P<0.001).
Figure 1. Actuarial Probability of Leukemia-free Survival in Unmatched Cohorts of Children Receiving Chemotherapy or Undergoing Transplantation.
The numbers below the figure indicate the numbers of children at risk.
For the 255 matched pairs from the two cohorts, the probabilityof leukemia-free survival at five years was significantly higherafter transplantation than after chemotherapy (40 ±3percent vs. 17 ±3 percent, P<0.001). Moreover, therisk of a relapse was significantly lower after transplantationthan after chemotherapy (45 ±4 percent vs. 80 ±3percent, P<0.001) (Figure 2 and Figure 3 and Table 3). Theprobability of treatment-related death within five years was14 ±4 percent with chemotherapy and 27 ±3 percentwith bone marrow transplantation (P<0.001).
Table 3. Probabilities of Relapse and Leukemia-free Survival Five Years after Chemotherapy or Bone Marrow Transplantation.
Table 3 shows the probabilities of leukemia-free survival andrelapse in subgroups of children according to the prognosticfactors listed in Table 1. A Cox proportional-hazards regressionmodel fitted with first-order interaction variables did notshow significant interactions between the treatment and anyof the prognostic variables studied -- that is, the relativebenefit of transplantation as compared with chemotherapy wassimilar in all groups. The probability of leukemia-free survivalat five years was higher after transplantation than after chemotherapyboth in children whose first remission had lasted 36 monthsor less (35 ±4 percent vs. 10 ±3 percent for 179pairs) (Figure 4A) and in those with a first remission thatexceeded 36 months (53 ±7 percent vs. 32 ±6 percent)(Figure 4B). Comparisons of pairs of children with a first remissionlonger than 48 months (36 pairs) or longer than 60 months (18pairs) yielded results that were similar to those for childrenwith a first remission that exceeded 36 months.
Figure 4. Actuarial Probability of Leukemia-free Survival in Matched Cohorts of Children Receiving Chemotherapy or Undergoing Transplantation, According to the Duration of the First Remission.
The numbers below the figure indicate the numbers of children at risk.
Discussion
Our study provides evidence that treatment with bone marrowtransplants from HLA-identical siblings results in a statisticallygreater likelihood of leukemia-free survival at five years thandoes chemotherapy in children with a bone marrow relapse aftera second remission of acute lymphoblastic leukemia. The reasonfor this difference was the lower risk of relapse after transplantation,which outweighed the higher risk of treatment-related mortalityassociated with this treatment. The outcome after transplantationwas superior to the outcome after chemotherapy in subgroupsof children with favorable or unfavorable prognostic factors(duration of first remission, 36 months or >36 months; leukocytecount at the time of the diagnosis, 100,000 per cubic millimeteror >100,000 per cubic millimeter; age, 10 years or >10years; and phenotype, T-cell or non-T-cell acute lymphoblasticleukemia). Since the numbers of matched pairs that could beevaluated in some of these subgroups were small (21 pairs withT-cell acute lymphoblastic leukemia and 17 with leukocyte countsover 100,000 per cubic millimeter), the relative benefits ofchemotherapy and transplantation remain uncertain in patientswith these characteristics.
This study indicates that leukemia-free survival is longer aftertransplantation than after chemotherapy but does not completelyanswer the question of the best treatment strategy for childrenwith acute lymphoblastic leukemia in a second remission. Ouranalysis does not consider a third option: to reserve transplantationfor children who have a second relapse after receiving chemotherapyfor their first relapse. However, the poor outcome of chemotherapyin children whose first remission lasts for 36 months or less(leukemia-free survival at five years, <10 percent) is anargument for early transplantation if an HLA-identical siblingis available. For children whose first remission is longer than36 months and in whom chemotherapy results in a better outcome(leukemia-free survival, about 30 percent), it may be reasonableto defer transplantation until a subsequent relapse occurs.
Because there are no randomized trials comparing chemotherapyand transplantation, we used a matched-pair design to controlboth for known prognostic factors in childhood acute lymphoblasticleukemia and for a time-to-treatment bias. Although the twocohorts were matched for these factors, there may have beenunknown factors that differed between the cohorts. Consequently,our findings should be interpreted cautiously.
Our conclusions apply only to the chemotherapy and transplantationregimens used for the patients we studied and only to the transplantationof grafts from HLA-identical siblings. Other chemotherapy andtransplantation regimens and autografts or transplants fromdonors other than HLA-identical siblings were not consideredand may have different outcomes. However, the methods used forthis study can readily be applied to comparisons of these otherapproaches.
Supported by grants (PO1-CA-40053, U10-CA-29139, CA-33625, CA-29281,CA-32053, CA-31566, and CA-30969) from the National Cancer Institute,the National Heart, Lung, and Blood Institute, and the NationalInstitute of Allergy and Infectious Diseases and by grants fromthe Alpha Therapeutic Corporation, Armour Pharmaceutical Company,Lynde and Harry Bradley Foundation, Bristol-Myers, BurroughsWellcome Company, Charles E. Culpeper Foundation, Eleanor NaylorDana Charitable Trust, Eppley Foundation for Research, Hoechst-RousselPharmaceuticals, Immunex Corporation, Kettering Family Foundation,Robert J. and Helen C. Kleberg Foundation, Eli Lilly and CompanyFoundation, Nada and Herbert P. Mahler Charities, Marion MerrellDow, Ambrose Monell Foundation, Samuel Roberts Noble Foundation,Ortho Biotech Corporation, John Oster Family Foundation, Janeand Lloyd Pettit Foundation, RGK Foundation, Roerig Divisionof Pfizer Pharmaceuticals, Sandoz Research Institute, StacknerFamily Foundation, Starr Foundation, Joan and Jack Stein Charities,Swiss Cancer League, and Wyeth-Ayerst Research.
This article is dedicated to the memory of Dr. Mortimer M. Bortin,who died July 25, 1994. Dr. Bortin was a pioneer of bone marrowtransplantation, participating in one of the first successfultransplantations in humans. He helped found the InternationalBone Marrow Transplant Registry in 1970 and served as its scientificdirector for over 20 years.
Source Information
From the National Heart, Lung, and Blood Institute, Bethesda, Md. (A.J.B.); the International Bone Marrow Transplant Registry, Health Policy Institute (M.M.H., M.-J.Z., M.M.B., P.A.R., K.A.S.), and the Departments of Pediatrics (B.M.C.) and Biostatistics (J.P.K.), Medical College of Wisconsin, Milwaukee; the Pediatric Oncology Group Statistical Office (B.H.P., J.J.S.) and the College of Medicine, University of Florida (J.G.-P.), Gainesville; the University of Texas Southwestern Medical Center, Dallas (G.R.B.); St. Jude's Children's Hospital, Memphis, Tenn. (J.O.); Case Western Reserve University School of Medicine, Cleveland (A.A.R.); and Salick Health Care, Los Angeles (R.P.G.). Dr. Mortimer M. Bortin is deceased.
Address reprint requests to Dr. Horowitz at the International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd., Milwaukee, WI 53226.
References
Rivera GK, Raimondi SC, Hancock ML, et al. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 1991;337:61-66. [CrossRef][Medline]
Chessells JM. Treatment of childhood acute lymphoblastic leukaemia: present issues and future prospects. Blood Rev 1992;6:193-203. [CrossRef][Medline]
Champlin R, Gale RP. Acute lymphoblastic leukemia: recent advances in biology and therapy. Blood 1989;73:2051-2066. [Free Full Text]
Rivera G, Murphy SB, Aur RJ, Verzosa MS, Dahl GV, Mauer AM. Recurrent childhood lymphocytic leukemia: clinical and cytokinetic studies of cytosine arabinoside and methotrexate for maintenance of second hematologic remission. Cancer 1978;42:2521-2528. [Medline]
Ekert H, Ellis MW, Waters KD, Matthews RN. Poor outlook for childhood acute lymphoblastic leukaemia with relapse. Med J Aust 1979;2:224-226. [Medline]
Chessells JM, Cornbleet M. Combination chemotherapy for bone marrow relapse in childhood lymphoblastic leukaemia (ALL). Med Pediatr Oncol 1979;6:359-365. [CrossRef][Medline]
Kimball JC, Herson J, Sullivan MP. Favorable response to maintenance therapy of second or subsequent remissions in childhood acute lymphocytic leukemia. Cancer 1980;45:1093-1097. [CrossRef][Medline]
Amadori S, Spiriti MA, Meloni G, Pacilli L, Papa G, Mandelli F. Combination chemotherapy for marrow relapse in children and adolescents with acute lymphocytic leukaemia. Scand J Haematol 1981;26:292-296. [Medline]
Baum E, Nachman J, Ramsay N, et al. Prolonged second remissions in childhood acute lymphocytic leukemia: a report from the Childrens Cancer Study Group. Med Pediatr Oncol 1983;11:1-7. [Medline]
Henze G, Fengler R, Hartmann R, et al. Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85): a relapse study of the BFM group. Blood 1991;78:1166-1172. [Free Full Text]
Sadowitz PD, Smith SD, Shuster J, Wharam MD, Buchanan GR, Rivera GK. Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 1993;81:602-609. [Free Full Text]
Ramsay NK, Kersey JH. Indications for bone marrow transplantation in acute lymphoblastic leukemia. Blood 1990;75:815-818. [Free Full Text]
Barrett AJ. Bone marrow transplantation for acute lymphoblastic leukaemia. In: Treleavan J, Barrett AJ, eds. Bone marrow transplantation in practice. Edinburgh, Scotland: Churchill Livingstone, 1992:33-47.
Sanders JE, Thomas ED, Buckner CD, Doney K. Marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood 1987;70:324-326. [Free Full Text]
Chessells JM, Rogers DW, Leiper AD, et al. Bone-marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia. Lancet 1986;1:1239-1241. [CrossRef][Medline]
Pinkel D. Allogeneic bone marrow transplantation in children with acute leukemia: a practice whose time has gone. Leukemia 1989;3:242-244. [Medline]
Coccia PF, Strandjord SE, Warkentin PI, et al. High-dose cytosine arabinoside and fractionated total-body irradiation: an improved preparative regimen for bone marrow transplantation of children with acute lymphoblastic leukemia in second remission. Blood 1988;71:888-893. [Free Full Text]
Barrett AJ, Horowitz MM, Gale RP, et al. Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 1989;74:862-871. [Free Full Text]
Barrett AJ, Joshi R, Kendra JR, et al. Prediction and prevention of relapse of acute lymphoblastic leukaemia after bone marrow transplantation. Br J Haematol 1986;64:179-186. [Medline]
Herzig RH, Bortin MM, Barrett AJ, et al. Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet 1987;1:786-789. [CrossRef][Medline]
Brochstein JA, Kernan NA, Groshen S, et al. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med 1987;317:1618-1624. [Abstract]
Dopfer R, Henze G, Bender-Gotze C, et al. Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: results of the German Cooperative Study. Blood 1991;78:2780-2784. [Free Full Text]
Wingard JR, Piantadosi S, Santos GW, et al. Allogeneic bone marrow transplantation for patients with high-risk acute lymphoblastic leukemia. J Clin Oncol 1990;8:820-830. [Abstract]
Poynton CH, Barrett AJ. Bone marrow transplantation in childhood lymphoblastic leukaemia. Lancet 1986;2:395-396. [Medline]
Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med 1981;305:846-851. [Abstract]
Darbyshire PJ, Pinkerton CR, Stevens RF, Oakhill A. Treatment of acute lymphoblastic leukaemia after relapse. Lancet 1990;335:733-733.
Buchanan GR, Boyett J, Rivera GK. Comparison of bone marrow transplantation and intensive chemotherapy for children with acute lymphoblastic leukemia in second marrow remission: a Pediatric Oncology Group (POG) study. Blood 1986;68:Suppl 1:219a-219a.abstract
Harris R, Feig S, Coccia P, et al. ALL in second remission -- a CCSG study of maintenance chemotherapy vs marrow transplantation. In: Gale RP, Champlin R, eds. Progress in bone marrow transplantation. New York: Alan R. Liss, 1987:91-5.
Butturini A, Rivera GK, Bortin MM, Gale RP. Which treatment for childhood acute lymphoblastic leukaemia in second remission? Lancet 1987;1:429-432. [Medline]
Horowitz MM, Bortin MM. The role of registries in evaluating the results of bone marrow transplantation. In: Treleavan J, Barrett AJ, eds. Bone marrow transplantation in practice. Edinburgh, Scotland: Churchill Livingstone, 1992:367-77.
Buchanan GR, Rivera GK, Boyett JM, Chauvenet AR, Crist WM, Vietti TJ. Reinduction therapy in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group Study. Blood 1988;72:1286-1292. [Free Full Text]
Begg CB, McGlave PB, Bennett JM, Cassileth PA, Oken MM. A critical comparison of allogeneic bone marrow transplantation and conventional chemotherapy as treatment for acute nonlymphocytic leukemia. J Clin Oncol 1984;2:369-378. [Abstract]
Horowitz MM, Messerer D, Hoelzer D, et al. Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 1991;115:13-18.
Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220.
Andersen PK, Borgan O, Gill RD, Keiding N. Statistical models based on counting processes. New York: Springer-Verlag, 1993:386-8.
von Stackelberg, A., Hartmann, R., Buhrer, C., Fengler, R., Janka-Schaub, G., Reiter, A., Mann, G., Schmiegelow, K., Ratei, R., Klingebiel, T., Ritter, J., Henze, G., for the ALL-REZ BFM Study Group,
(2008). High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood
111: 2573-2580
[Abstract][Full Text]
Malempati, S., Gaynon, P. S., Sather, H., La, M. K., Stork, L. C.
(2007). Outcome After Relapse Among Children With Standard-Risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study CCG-1952. JCO
25: 5800-5807
[Abstract][Full Text]
Fujii, H., Trudeau, J. D., Teachey, D. T., Fish, J. D., Grupp, S. A., Schultz, K. R., Reid, G. S. D.
(2007). In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides. Blood
109: 2008-2013
[Abstract][Full Text]
Fung, H. C., Higman, M. A., van Besien, K.
(2007). Stem cell transplantation. ASH-SAP
2007: 328-360
[Full Text]
Montagna, D., Daudt, L., Locatelli, F., Montini, E., Turin, I., Lisini, D., Giorgiani, G., Bernardo, M. E., Maccario, R.
(2006). Single-Cell Cloning of Human, Donor-Derived Antileukemia T-Cell Lines for In vitro Separation of Graft-versus-Leukemia Effect from Graft-versus-Host Reaction.. Cancer Res.
66: 7310-7316
[Abstract][Full Text]
Gaynon, P. S., Harris, R. E., Altman, A. J., Bostrom, B. C., Breneman, J. C., Hawks, R., Steele, D., Zipf, T., Stram, D. O., Villaluna, D., Trigg, M. E.
(2006). Bone Marrow Transplantation Versus Prolonged Intensive Chemotherapy for Children With Acute Lymphoblastic Leukemia and an Initial Bone Marrow Relapse Within 12 Months of the Completion of Primary Therapy: Children's Oncology Group Study CCG-1941. JCO
24: 3150-3156
[Abstract][Full Text]
Eapen, M., Raetz, E., Zhang, M.-J., Muehlenbein, C., Devidas, M., Abshire, T., Billett, A., Homans, A., Camitta, B., Carroll, W. L., Davies, S. M., for the Children's Oncology Group and the Center f,
(2006). Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood
107: 4961-4967
[Abstract][Full Text]
Einsiedel, H. G., von Stackelberg, A., Hartmann, R., Fengler, R., Schrappe, M., Janka-Schaub, G., Mann, G., Hahlen, K., Gobel, U., Klingebiel, T., Ludwig, W.-D., Henze, G.
(2005). Long-Term Outcome in Children With Relapsed ALL by Risk-Stratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Munster Group 87. JCO
23: 7942-7950
[Abstract][Full Text]
Svahn, B.-M., Remberger, M., Myrback, K.-E., Holmberg, K., Eriksson, B., Hentschke, P., Aschan, J., Barkholt, L., Ringden, O.
(2002). Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood
100: 4317-4324
[Abstract][Full Text]
Bunin, N., Carston, M., Wall, D., Adams, R., Casper, J., Kamani, N., King, R., the National Marrow Donor Program Working Group,
(2002). Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood
99: 3151-3157
[Abstract][Full Text]
Woolfrey, A. E., Anasetti, C., Storer, B., Doney, K., Milner, L. A., Sievers, E. L., Carpenter, P., Martin, P., Petersdorf, E., Appelbaum, F. R., Hansen, J. A., Sanders, J. E.
(2002). Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood
99: 2002-2008
[Abstract][Full Text]
Bickert, B. M.
(2002). Treatment of Common Childhood Malignancies. Journal of Pharmacy Practice
15: 42-51
[Abstract]
Hoelzer, D., Gokbuget, N., Ottmann, O., Pui, C.-H., Relling, M. V., Appelbaum, F. R., van Dongen, J. J.M., Szczepanski, T.
(2002). Acute Lymphoblastic Leukemia. ASH Education Book
2002: 162-192
[Abstract][Full Text]
Saarinen-Pihkala, U. M., Gustafsson, G., Ringden, O., Heilmann, C., Glomstein, A., Lonnerholm, G., Abrahamsson, J., Bekassy, A. N., Schroeder, H., Mellander, L.
(2001). No Disadvantage in Outcome of Using Matched Unrelated Donors as Compared With Matched Sibling Donors for Bone Marrow Transplantation in Children With Acute Lymphoblastic Leukemia in Second Remission. JCO
19: 3406-3414
[Abstract][Full Text]
Godder, K. T., Hazlett, L. J., Abhyankar, S. H., Chiang, K. Y., Christiansen, N. P., Bridges, K. D., Lee, C. G., Geier, S. S., Goon-Johnson, K. S., Gee, A. P., Pati, A. R., Parrish, R. S., Henslee-Downey, P. J.
(2000). Partially Mismatched Related-Donor Bone Marrow Transplantation for Pediatric Patients With Acute Leukemia: Younger Donors and Absence of Peripheral Blasts Improve Outcome. JCO
18: 1856-1866
[Abstract][Full Text]
Locatelli, F., Zecca, M., Rondelli, R., Bonetti, F., Dini, G., Prete, A., Messina, C., Uderzo, C., Ripaldi, M., Porta, F., Giorgiani, G., Giraldi, E., Pession, A.
(2000). Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood
95: 1572-1579
[Abstract][Full Text]
Socie, G., Curtis, R. E., Deeg, H. J., Sobocinski, K. A., Filipovich, A. H., Travis, L. B., Sullivan, K. M., Rowlings, P. A., Kingma, D. W., Banks, P. M., Travis, W. D., Witherspoon, R. P., Sanders, J., Jaffe, E. S., Horowitz, M. M.
(2000). New Malignant Diseases After Allogeneic Marrow Transplantation for Childhood Acute Leukemia. JCO
18: 348-348
[Abstract][Full Text]
Felix, C. A., Lange, B. J., Chessells, J. M.
(2000). Pediatric Acute Lymphoblastic Leukemia: Challenges and Controversies in 2000. ASH Education Book
2000: 285-302
[Abstract][Full Text]
Green, A., Clarke, E., Hunt, L., Canterbury, A., Lankester, A., Hale, G., Waldmann, H., Goodman, S., Cornish, J. M., Marks, D. I., Steward, C. G., Oakhill, A., Pamphilon, D. H.
(1999). Children With Acute Lymphoblastic Leukemia Who Receive T-Cell-Depleted HLA Mismatched Marrow Allografts From Unrelated Donors Have an Increased Incidence of Primary Graft Failure but a Similar Overall Transplant Outcome. Blood
94: 2236-2246
[Abstract][Full Text]
Socie, G., Stone, J. V., Wingard, J. R., Weisdorf, D., Henslee-Downey, P. J., Bredeson, C., Cahn, J.-Y., Passweg, J. R., Rowlings, P. A., Schouten, H. C., Kolb, H.-J., Klein, J. P., Bender-Gotze, C., Camitta, B. M., Godder, K., Horowitz, M. M., Wayne, A. S., The Late Effects Working Committee of the Internat,
(1999). Long-Term Survival and Late Deaths after Allogeneic Bone Marrow Transplantation. NEJM
341: 14-21
[Abstract][Full Text]
Zecca, M., Pession, A., Messina, C., Bonetti, F., Favre, C., Prete, A., Cesaro, S., Porta, F., Mazzarino, I., Giorgiani, G., Rondelli, R., Locatelli, F.
(1999). Total Body Irradiation, Thiotepa, and Cyclophosphamide as a Conditioning Regimen for Children With Acute Lymphoblastic Leukemia in First or Second Remission Undergoing Bone Marrow Transplantation With HLA-Identical Siblings. JCO
17: 1838-1838
[Abstract][Full Text]
Locatelli, F., Rocha, V., Chastang, C., Arcese, W., Michel, G., Abecasis, M., Messina, C., Ortega, J., Badell-Serra, I., Plouvier, E., Souillet, G., Jouet, J.-P., Pasquini, R., Ferreira, E., Garnier, F., Gluckman, E.
(1999). Factors Associated With Outcome After Cord Blood Transplantation in Children With Acute Leukemia. Blood
93: 3662-3671
[Abstract][Full Text]
Boulad, F., Steinherz, P., Reyes, B., Heller, G., Gillio, A. P., Small, T. N., Brochstein, J. A., Kernan, N. A., O'Reilly, R. J.
(1999). Allogeneic Bone Marrow Transplantation Versus Chemotherapy for the Treatment of Childhood Acute Lymphoblastic Leukemia in Second Remission: A Single-Institution Study. JCO
17: 197-197
[Abstract][Full Text]
Knechtli, C. J.C., Goulden, N. J., Hancock, J. P., Grandage, V. L.G., Harris, E. L., Garland, R. J., Jones, C. G., Rowbottom, A. W., Hunt, L. P., Green, A. F., Clarke, E., Lankester, A. W., Cornish, J. M., Pamphilon, D. H., Steward, C. G., Oakhill, A.
(1998). Minimal Residual Disease Status Before Allogeneic Bone Marrow Transplantation Is an Important Determinant of Successful Outcome for Children and Adolescents With Acute Lymphoblastic Leukemia. Blood
92: 4072-4079
[Abstract][Full Text]
Pui, C.-H., Evans, W. E.
(1998). Acute Lymphoblastic Leukemia. NEJM
339: 605-615
[Full Text]
Kersey, J. H.
(1997). Fifty Years of Studies of the Biology and Therapy of Childhood Leukemia. Blood
90: 4243-4251
[Full Text]
Weisdorf, D. J., Billett, A. L., Hannan, P., Ritz, J., Sallan, S. E., Steinbuch, M., Ramsay, N. K.C.
(1997). Autologous Versus Unrelated Donor Allogeneic Marrow Transplantation for Acute Lymphoblastic Leukemia. Blood
90: 2962-2968
[Abstract][Full Text]
Pavletic, Z. S., Armitage, J. O.
(1996). Bone Marrow Transplantation for Cancer--An Update. The Oncologist
1: 159-168
[Abstract][Full Text]
Foot, A. B.
(1995). The changing face of paediatric oncology. Palliat Med
9: 193-199
[Abstract]
Pinkel, D., Johnson, F. L., Thomas, E. D., Barrett, A. J., Pollock, B. H., Buchanan, G. R.
(1995). Treatment of Acute Lymphoblastic Leukemia in a Second Remission. NEJM
332: 823-824
[Full Text]
18 months) but not in those with a long first remission29. However, prognostic and treatment information that might have accounted for the difference was not available for the patients receiving chemotherapy. 
Previous
