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© 2002 American Society for Clinical Oncology Prospective Trial of Chemotherapy and Donor Leukocyte Infusions for Relapse of Advanced Myeloid Malignancies After Allogeneic Stem-Cell TransplantationByFrom the University of Michigan, Ann Arbor, MI; Ohio State University, Columbus, OH; University of Utah, Salt Lake City, UT; Indiana University, Indianapolis, IN; Hospital de Sant Pau, Barcelona, Spain; Medical College of Wisconsin and International Bone Marrow Transplant Registry, Milwaukee, WI; National Heart, Lung and Blood Institute, Bethesda, MD; University of Pennsylvania, Philadelphia, PA; M.D. Anderson Cancer Center, Houston; Baylor-Sammons Cancer Center, Dallas; and University of Texas Southwestern Medical Center, Dallas, TX; and Oregon Health Sciences University, Portland, OR. Supported by the Leukemia Association of North Central Texas.Address reprint requests to John E. Levine, MD, Blood and Marrow Stem Cell Transplantation Program, B1-207 CCGC/Box 0914, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0914; email: jelevine{at}umich.edu
PURPOSE: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)–primed DLIs. PATIENTS AND METHODS: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF–primed DLIs. No prophylactic immunosuppression was provided. RESULTS: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A posttransplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission. CONCLUSION: Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem.
LEUKEMIA RELAPSE after allogeneic bone marrow transplantation (BMT) has a high mortality rate and presents a serious therapeutic challenge. Stopping immunosuppression, reinduction chemotherapy, a second BMT, or some combination of these strategies occasionally lead to durable remission, but more often, these strategies prove unsuccessful.1-3 Donor leukocyte infusions (DLIs) can exert a graft-versus-leukemia (GVL) effect when used to treat a variety of malignant relapses after BMT.4-15 When used as primary therapy, DLIs are effective in the treatment of molecular, cytogenetic, or chronic-phase relapse of chronic myeloid leukemia (CML) with durable response rates as high as 80%.13 When donor leukocytes are used to treat more advanced myeloid leukemia relapses, such as CML in accelerated phase or blast crisis or hematologic relapse of acute myeloid leukemia, far lower response rates have been observed, and the durability of response is unclear.11 We suspected that poor response to DLI for advanced leukemia might be attributable in part to a proliferation rate too rapid for DLI alone to be effective. We hypothesized that leukemia cytoreduction before DLI would result in a more favorable starting point for the GVL effect to occur and would lead to superior survival. We tested this hypothesis with a prospective trial in which patients with hematologic myeloid leukemia relapse were treated with cytoreductive chemotherapy before granulocyte colony-stimulating factor (G-CSF)–primed DLIs.
Eligibility Criteria The study was approved by the institutional review boards at all participating centers, and informed consent was obtained from all patients. The eligibility criteria were an age of 65 years or less and diagnosis of CML, acute myelogenous leukemia (AML), or myelodysplastic syndrome (MDS) in relapse after allogeneic BMT from an HLA-matched relative. Patients with CML were required to be in accelerated phase or blast phase (as defined by clinical criteria16; however, patients with additional cytogenetic abnormalities were not classified as being in an accelerated phase unless other criteria were also met), and patients with AML and MDS were required to be in hematologic relapse. For AML, hematologic relapse was defined as circulating blasts or more than 5% blasts in the bone marrow. For MDS, hematologic relapse was defined as recurrence of bone marrow abnormalities consistent with previous MDS morphology. Patients with cytogenetic or molecular-only relapse were excluded. Patients also had to be free from active acute or chronic graft-versus-host disease (GVHD), have a sustainable platelet count of at least 20,000/µL, and have a creatinine level of less than 2.5 mg/dL. Donors had to be the original bone marrow donor, be in good health (as assessed by history and physical examination), possess a normal complete blood count, and be negative for human immunodeficiency virus. Study sites determined which potentially eligible patients were enrolled onto this trial.
Study Design Donors received G-CSF 10 µg/kg per day subcutaneously for 5 days before apheresis collection. The target lymphocyte dose was 1 x 108 CD3+ cells/kg. No target CD34+ cell dose was set, and in two cases included in the analysis, the donors were not mobilized. Pheresis collections were performed 10 to 14 days after chemotherapy, when nadir of the blood counts was anticipated. The apheresis product was provided fresh, and remaining cells were cryopreserved for a second infusion of 5 x 108 CD3+ cells/kg for patients with residual leukemia and no GVHD 4 weeks after the first DLI. No post-DLI GVHD prophylaxis was administered. By study design, grade 1 GVHD was generally not treated for 7 days. Grade 2 to 4 GVHD was treated with corticosteroids and other immunosuppressive agents at the clinician’s discretion. GVHD was graded according to the standard criteria.17,18
Definitions of Outcome
Statistics
Accrual Sixty-five patients from 34 BMT centers were entered onto this prospective trial between May 1996 and December 1999.
Patient Characteristics
Pre-DLI and DLI Characteristics Before study entry, nine patients experienced relapse with a more advanced leukemia than the original diagnosis. Four transplant recipients with CML in chronic phase relapsed with blast crisis, as did one transplant recipient with CML in accelerated phase. One transplant recipient with CML in chronic phase experienced relapse with accelerated-phase CML. Three patients with MDS (one with refractory anemia and two with refractory anemia with excess of blasts in transformation) experienced relapse with AML. Patients were treated with myelosuppressive, but not myeloablative, chemotherapy before receiving G-CSF–primed DLIs. Combination chemotherapy with cytarabine and an anthracycline was recommended for pre-DLI chemotherapy, but other agents were used at the investigator’s discretion. The chemotherapy regimens used are summarized in Table 2. Most patients received cytarabine-based chemotherapy, but cladarabine- and anthracycline-based regimens were also used.
DLI was provided a median of 28 days after relapse (range, 11 to 111 days). The target T-cell dose was 1.0 x 108 T cells/kg. The actual median T-cell dose was 1.0 x 108 CD3+ cells/kg (0.6 to 4.2 x 108) for the 61 patients for whom doses were recorded. The median CD34+ cell dose/kg was 2.8 x 106 (range, 0.9 to 12 x 106/kg) for the 21 patients with recorded values. Twelve patients received a second DLI because of lack of response to the first infusion. The target T-cell dose for second infusions was 5.0 x 108 T-cells/kg. In seven of the 12 patients for whom the dose was recorded, the actual median T-cell dose was 2.35 x 108 CD3+ cells/kg (1.0 to 6.6 x 108 cells/kg).
Disease Responses to Study Therapy Thirty patients did not respond to study therapy, resulting in 25 deaths as a result of progressive disease (median time to death, 77 days from DLI). Ten of the nonresponding patients received a second DLI, resulting in CR in three patients and no response in the remaining seven. One of the three patients who responded to a second DLI died while in remission from GVHD 75 days after the second DLI. Another patient experienced relapse 159 days after the second DLI and died as a result of disease. A third patient remained in remission at last follow-up, 59 days from the second DLI. Of the other three patients who did not die from progressive disease, one was alive in relapse 93 days after DLI, one underwent a second BMT for resistant leukemia and is alive in CR 176 days after DLI, and one withdrew from the study at day 14 to pursue other treatments.
Responses by Duration of Posttransplant Remission
Twenty-nine patients relapsed more than 6 months from their BMT surgery. Two of these patients died before day 30. Seventeen patients (59%) responded, and eight patients (28%) remain in remission. A ninth patient with sensitive leukemia remained in CR for 761 days, and then experienced recurrence of disease in the testicles. He underwent a second BMT and remains in remission, more than 999 days after DLI and more than 238 days after post-DLI relapse. Ten patients (34%) did not respond; none are in CR.
Toxicity and GVHD Thirty-three of 58 assessable patients developed acute GVHD. There were seven cases of grade 1, 10 cases of grade 2, seven cases of grade 3, and nine cases of grade 4 acute GVHD. Acute GVHD developed in 16 (59%) of 27 patients who responded, in 16 (53%) of 30 patients who did not respond, and in one patient who died before day 30. Eleven of 27 patients who achieved a CR did so without any acute GVHD. Acute GVHD was the proximate cause of death in five patients with CR (18%) and contributed to the death of one patient who died while experiencing relapse. Twenty-eight patients were assessable for chronic GVHD. Eighteen patients developed no evidence of chronic GVHD, six developed limited chronic GVHD, and four patients developed extensive chronic GVHD. Four of 10 patients who responded to therapy with remissions that lasted 6 months or more had acute GVHD, and four had chronic GVHD. Of six patients who did not develop either acute or chronic GVHD, three patients experienced remissions lasting 6 months or more.
Aplasia
Survival
Factors Predictive of Response We wished to determine patient characteristics that would allow us to predict whether a subject would respond to the study therapy. We performed a multivariate analysis of the effect of age, original transplant stem-cell source (bone marrow v peripheral-blood stem cells), original conditioning (total-body irradiation v no total-body irradiation), disease status at original transplant (advanced v nonadvanced), presence of posttransplant acute GVHD, presence of posttransplant chronic GVHD, study chemotherapy (cytarabine-containing or not), presence of post-DLI acute GVHD, presence of post-DLI chronic GVHD, T-cell dose, duration of posttransplant remission (< 6 months v at least 6 months), and days from relapse to DLI on the likelihood of response and the likelihood of relapse in those who responded. We defined original disease as nonadvanced if the patient was in CR at the time of original transplant, CML in chronic phase, or refractory anemia. All other disease states were considered advanced. The final model included main effects for duration of post-BMT remission and the days from relapse to DLI. The goodness of fit of this final model was statistically significant (P = .021). Patients with a post-BMT remission of at least 6 months have an odds of remission 3.7 times that of patients whose remission after BMT is less than 6 months (odds ratio, 3.7; 95% CI, 1.1 to 11.8). The probability of post-DLI remission generally increases as the time from relapse to DLI increases. The above patient characteristics were also used in a Cox regression model for the length of remission in those who responded. As a result of low statistical power, we lack evidence that any of the characteristics analyzed are predictive of the probability of relapse in those who responded to therapy.
Factors Predictive of Survival
We also examined whether disease at time of study entry (AML v MDS v CML), pre-DLI chemotherapy (cytarabine-containing v not), or acute or chronic GVHD after DLI influenced overall survival. Overall survival was not statistically different among the three disease groups, AML, MDS, CML (P = .153), or for pre-DLI chemotherapy. Although the difference was marginally significant (P = .01), it seems that those who developed acute GVHD had a lower probability of survival than those who did not develop acute GVHD. Specifically, 1-year survival after DLI was 12% (95% CI, 4% to 33%) in those with acute GVHD and 42% (95% CI, 21% to 72%) in those without acute GVHD. Among study subjects who achieved remission, we found that the probability of relapse was similar whether or not they developed acute GVHD. Because death in remission was a competing risk, we estimated the probability of relapse conditional on a patient’s having survived. The 1-year conditional rate of relapse was 49% (95% CI, 14% to 95%) in those with acute GVHD, compared with 41% (95% CI, 13% to 86%) in those without acute GVHD.
The best management of advanced myeloid malignancy in relapse after allogeneic BMT is uncertain. Attempts to harness the GVL effect in this setting by infusing donor lymphocytes have been largely unsuccessful.4-6,8 GVL effects from DLI generally take several weeks to evolve10,12; it is possible that DLI works poorly in advanced myeloid malignancy, in part because rapid tumor growth rate outstrips the rate at which GVL effects can develop. If so, then debulking tumor with chemotherapy before DLI may be advantageous. We investigated this concept by prospectively evaluating pre-DLI chemotherapy in a cohort of patients with advanced myeloid malignancies. A limitation of this study is that a uniform chemotherapy regimen was not used; this was necessitated by the heterogeneity of previous treatment and the need to allow clinicians to choose chemotherapy on the basis of individual clinical circumstances. However, all patients received standard intensive chemotherapy regimens that have well-documented activity in myeloid malignancies. We found that 42% of patients treated by chemotherapy and DLI had CR to this therapy, with disease-free survival of 34% at 1 and 2 years; overall survival was 51% at 1 year and 41% at 2 years. GVHD was observed in 56% of patients, and overall treatment-related mortality was 23%. Patients whose initial post-BMT remission duration was less then 6 months were unlikely to benefit from this approach. Occurrence of GVHD did not translate into improved survival. The results from combined chemotherapy and DLI can be compared with results that used DLI alone, chemotherapy alone, or second transplants, keeping in mind the inherit limitations of historical comparisons. The literature reports that DLI alone in advanced myeloid malignancy has a response rate of 0% to 25%.4-6,8 Although duration of remission has been inconsistently reported, relapses among responders is common.5-8 With the support of the International Bone Marrow Transplant Registry, we have maintained a database of more than 300 recipients of DLI. These data show that only two of 14 accelerated-phase CML patients and zero of nine blast-phase CML patients were in remission when treated with DLI alone. Likewise, only one of 34 patients with AML and two of 10 with MDS in hematologic relapse remained in remission at 6 months after DLI as the sole therapy for relapse (unpublished data). The 6-month disease-free survival of 32% in our study seems superior to the 6-month disease-free survival of 7% in these historical controls. Thus, chemotherapy and DLI seem superior to DLI alone in this category of patients. However, the relative contributions of chemotherapy and DLI-induced GVL are unclear. Relatively little has been published about the use of chemotherapy alone for advanced myeloid relapse after BMT. Mortimer et al2 reported that 15 (34%) of 44 patients with AML in relapse after BMT achieved a CR with combination chemotherapy, a remission rate similar to that in our study. However, after excluding two patients who went on to receive a second transplant, only one (2%) of 42 patients treated with combination chemotherapy alone was alive at 1 year compared with 25% of the patients in our study. In the study of Mortimer et al,2 the median time from transplant to relapse was 6.5 months compared with 3.4 months in this study population. Thus, these data suggest that few patients achieve durable remission when treated with chemotherapy alone. In comparing our results to those of second transplants, it should be noted that in many respects, the approach taken in this trial is similar to a second BMT. The critical differences between our approach and a second BMT are the use of subablative, instead of myeloablative, chemotherapy, therapy in untreated relapse, and the absence of posttransplant prophylactic immunosuppression. For patients who experience relapse after their first BMT, others have reported 2-year survival as high as 47% after second myeloablative BMT.20 However, many of the patients who responded to second BMTs were treated for CML relapse in chronic phase, a condition that now would be treated with DLI alone. When one looks at patients with disease states similar to those reported in this study, 2-year survival after second transplant ranges from 2% to 25%.3,20-23 In studies of second BMTs, transplant-related mortality occurred in 41% to 56% of the patients.3,20-24 In this study, 2-year survival was 19% with treatment-related mortality of 23%. Last, we should note that remissions have be observed in patients who experience relapse after BMT treated with G-CSF alone. Giralt et al25 reported CRs in three of seven patients with CML or AML, and Bishop et al26 reported CRs in six of 14 patients with MDS or leukemia treated with cessation of any immunosuppression and G-CSF. The mechanisms of these responses are unclear. Donors in our study received G-CSF before donor leukocyte collection with the intent of collecting stem cells, on the assumption that infusion of stem cells might prevent aplasia. Aplasia that was not attributable to chemotherapy, infection, or relapse was uncommon in this study population. In a sequential study of patients with relapsed CML treated with DLI, Flowers et al27 added G-CSF to prevent aplasia; they used the same reasoning we did. In their study, the addition of G-CSF did not seem to have a protective effect against aplasia. They suggested that the aplasia after DLI involves failure of donor hematopoiesis by undefined mechanisms. Our study neither confirms nor refutes the findings of Flowers et al,27 given the differences in study design and patient populations. Further investigations will be needed to determine the role of G-CSF in preventing aplasia associated with DLI. We should note that administration of G-CSF before stem-cell collection may alter the immune activity of lymphocytes. Murine and human studies have suggested that G-CSF administration results in polarization of T cells toward TH2 cells.28-30 Whether this would result in more or less GVL or GVHD activity is uncertain, although murine studies suggest that such polarization might lead to a GVL effect without GVHD.29,30 Interestingly, the development of acute GVHD did not increase the probability of achieving or remaining in remission in our study. In a univariate analysis, the development of acute GVHD was associated with an inferior outcome. This result differs from other DLI studies that found a strong correlation between GVHD and response.5,8 One possible explanation is that the main contribution to survival was the chemotherapy effect and GVHD-GVL played little role in prolonged remission. This explanation cannot be excluded, but the historical data discussed above suggest that chemotherapy alone rarely results in prolonged survival. An alternative explanation is that GVL occurred without GVHD in some instances, a possibility that has been suggested by previous studies.31 As discussed above, on the basis of murine studies, it is conceivable that mobilization of donors with G-CSF resulted in a TH2 polarization favorable for GVL development.29,30 Last, of course, it is possible that the ameliorative effect of GVHD-associated GVL was canceled out in some cases by GVHD-induced fatality. In summary, chemotherapy followed by DLI seems to compare favorably with other treatment approaches used in this setting. However, the relative contributions of chemotherapy, DLI, and G-CSF mobilization are uncertain. To ascertain the overall usefulness of this approach versus other approaches, randomized clinical trials would be required. We emphasize that patients with short initial post-BMT remissions (< 6 months) are unlikely to respond to this approach, and the approach should thus be considered only in patients with longer post-BMT remission. We believe it is especially important to emphasize the limitations of this approach. GVHD is common, and the treatment-related mortality rate is 23%. Moreover, the majority of patients either do not respond or experience relapse after initially responding. Thus, the addition of chemotherapy for the purpose of debulking is, by itself, an insufficient intervention in the majority of such patients. The causes for insufficient GVL in this setting are uncertain. It is possible that the majority of patients with advanced myeloid malignancies who can be cured through GVL effects are cured with the initial transplant; those who relapse may simply not be responsive to the GVL effect for a variety of reasons, including poor antigen presentation, ineffective costimulation, inadequate adhesion molecule expression, induction of tolerance, or deficiencies in other areas central to development of a significant GVL effect. Thus, we believe that significant progress in this area will require improved understanding of the mechanisms of resistance to donor-derived immune antitumor effects.
APPENDIX
We thank Angela Sproles for data management.
1. Brandenburg U, Gottlieb D, Bradstock K: Antileukemic effects of rapid cyclosporin withdrawal in patients with relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation. Leuk Lymphoma 31: 545–550, 1998[Medline] 2. Mortimer J, Blinder MA, Schulman S, et al: Relapse of acute leukemia after marrow transplantation: Natural history and results of subsequent therapy. J Clin Oncol 7: 50–57, 1989[Abstract] 3. Barrett AJ, Locatelli F, Treleaven JG, et al: Second transplants for leukaemic relapse after bone marrow transplantation: High early mortality but favourable effect of chronic GVHD on continued remission. Br J Haematol 79: 567–574, 1991[Medline]
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8.
Collins RH, Shpilberg O, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15: 433–444, 1997 9. Raanani P, Dazzi F, Sohal J, et al: The rate and kinetics of molecular response to donor leucocyte transfusions in chronic myeloid leukemia patients treated for relapse after allogeneic bone marrow transplantation. Br J Haematol 99: 945–950, 1997[CrossRef][Medline] 10. Rapanotti MC, Arcese W, Buffolino S, et al: Sequential molecular monitoring of chimerism in chronic myeloid leukemia patients receiving donor lymphocyte transfusion for relapse after bone marrow transplantation. Bone Marrow Transplant 19: 703–707, 1997[CrossRef][Medline] 11. Kolb H-J: Donor leukocyte transfusions for treatment of leukemic relapses after bone marrow transplantation. Vox Sang 74: 321–329, 1998 (suppl 2)
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Dazzi F, Szydlo RM, Cross NC, et al: Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 96: 2712–2716, 2000 16. Speck B, Bortin MM, Champlin R, et al: Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet 1: 665–668, 1984[Medline] 17. Thomas ED, Storb R, Clift RA, et al: Bone marrow transplantation. N Engl J Med 292: 895–902, 1975[Medline] 18. Shulman HM, Sullivan KM, Weiden PL, et al: Chronic graft-versus-host syndrome in man: A long-term clinicopathologic study of 20 Seattle patients. Am J Med 69: 204–217, 1980[CrossRef][Medline] 19. Pepe M, Mori M: Kaplan-Meier, marginal, or conditional probability curves in summarizing competing risks failure time data. Stat Med 12: 737–751, 1993[Medline] 20. Wagner JE, Vogelsang GB, Zehnbauer BA, et al: Relapse of leukemia after bone marrow transplantation: Effect of second myeloablative therapy. Bone Marrow Transplant 9: 205–209, 1992[Medline] 21. Frassoni F, Barrett AJ, Granena A, et al: Relapse after allogeneic bone marrow transplantation for acute leukemia: A survey by the EBMT of 117 cases. Br J Haematol 70: 317–320, 1988[Medline] 22. Mrsic M, Horowitz MM, Atkinson K, et al: Second HLA-identical transplants for leukemia recurrence. Bone Marrow Transplant 9: 269–275, 1992[Medline] 23. Michallet M, Tanguy ML, Socié G, et al: Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: A survey of the Societé Française de Greffe de Moelle (SFGM). Br J Haematol 108: 400–407, 2000[CrossRef][Medline] 24. Chiang K-Y, Weisdorf DJ, Davies SM, et al: Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse. Bone Marrow Transplant 17: 39–42, 1996[Medline]
25.
Giralt S, Escudier S, Kantarjian H, et al: Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation. N Engl J Med 329: 757–761, 1993
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Bishop MR, Tarantolo SR, Pavletic ZS, et al: Filgrastim as an alternative to donor leukocyte infusion for relapse after allogeneic stem-cell transplantation. J Clin Oncol 18: 2269–2272, 2000 27. Flowers ME, Leisenring W, Beach K, et al: Granulocyte colony-stimulating factor given to donors before apheresis does not prevent aplasia in patients treated with donor leukocyte infusion for recurrent chronic myeloid leukemia after bone marrow transplantation. Biol Blood Marrow Transplant 6: 321–326, 2000[CrossRef][Medline]
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Pan L, Teshima T, Hill GR, et al: Granulocyte colony-stimulating factor–mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease. Blood 93: 4071–4078, 1999 30. Reddy V, Hill GR, Pan L, et al: G-CSF modulates cytokine profile of dendritic cells and decreases acute graft-versus-host disease through effects on the donor rather than the recipient. Transplantation 69: 691–693, 2000[CrossRef][Medline]
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Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75: 555–562, 1990 Submitted February 23, 2001; accepted September 5, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
