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Interleukin-2 After Autologous Stem-Cell Transplantation for Adult Patients With Acute Myeloid Leukemia in First Complete Remission

Anthony S. Stein, Margaret R. O’Donnell, Marilyn L. Slovak, David S. Snyder, Auayporn P. Nademanee, Pablo Parker, Arturo Molina, George Somlo, Henry C. Fung, Amrita Krishnan, Roberto Rodriguez, Ricardo T. Spielberger, Shirong Wang, Andrew Dagis, Nayana Vora, Daniel A. Arber, Joyce C. Niland, Stephen J. Forman

From the City of Hope National Medical Center, Duarte, CA.

Address reprint requests to Anthony S. Stein, MD, Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010; email: astein{at}coh.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation.

Patients and Methods: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10⁶ U/m²/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10⁶ U/m²/24 h on hematologic recovery.

Results: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate.

Conclusion: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin–mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ADULTS WITH de novo acute myeloid leukemia (AML) achieve a complete remission (CR) in 60% to 90% of cases using current induction chemotherapy strategies.^1–10 Intensification of postremission chemotherapy including the use of high-dose cytarabine (HD ARA-C) has led to improved disease-free survival (DFS), with a purported cure rate of 20% to 44%.^11–13 Allogeneic bone marrow transplantation (BMT) in adult AML patients in first complete remission (CR1) has resulted in 5-year DFS rates of 45% to 65% and relapse rates of 10% to 25%.^14–17

Interest in autologous stem-cell transplantation (ASCT) as consolidation in CR for AML has increased in the last decade.¹⁸ Unlike allogeneic BMT, for which treatment-related complications are the major cause of mortality,¹⁹ leukemic relapse and delayed hematopoietic reconstitution are the major causes of treatment failure after autologous transplantation. Twin transplants²⁰ and cell-marking studies²¹ have identified residual body burden and/or reinfusion of leukemic cells in the stem-cell graft as potential origins of relapse after autologous transplant. The decreased relapse rate observed with allogeneic transplants supports the concept of an immunotherapeutic role of the allograft contributing to the prevention of relapse. Further evidence supporting the graft versus leukemia model includes disease regression after withdrawal of immunosuppression or after donor lymphocyte infusions for relapse after ASCT.^22–24

Interleukin-2 (IL-2) is a cytokine with broad-spectrum antitumor activity. When administered to ASCT patients, IL-2 appears to reproduce the graft versus malignancy effect observed in allogeneic transplants.²⁵ The concept that IL-2 induces a graft versus malignancy effect is supported by preclinical data showing that malignant human hematopoietic cells can be lysed in vitro by IL-2–activated effector cells.^26–28 In vivo data also show lysis of chemotherapy-resistant tumor cells by IL-2-activated endogenous natural killer and T cells.²⁹ IL-2–responsive cells can be detected in the blood soon after transplantation.³⁰ Several centers have explored the use of IL-2 after hematologic recovery. Robinson et al³¹ treated 22 patients with acute leukemia in relapse or beyond CR1 who underwent ASCT using cells harvested during CR. IL-2 was given by continuous intravenous infusion after hematologic recovery at doses ranging from 9 to 12 million U/m²/d for 4 to 5 days, followed 1 week later by a 10-day infusion of 1.6 million U/m²/d. Among 17 patients with AML, four remained in continuous remission from 12 to 25 months after therapy. On the basis of these studies, we explored the feasibility and toxicity of administering that particular IL-2 immunotherapy early after ASCT on an intent-to-treat basis as a component of a consolidation strategy that incorporated a single cycle of HD ARA-C and idarubicin consolidation followed by a radiation-based ASCT.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Fifty-six consecutive patients were entered on study between August 1994 and November 1999. Patients between age 16 and physiologic age 60 years were eligible if they had de novo AML (French-American-British [FAB] M0 to M7) in CR1 and had not received any prior consolidation treatment. First remission was defined by standard criteria;³² however, patients were also required to have normal marrow cytogenetics (20 metaphases were analyzed). Patients were excluded if they had acute promyelocytic leukemia (FAB M3), antecedent myelodysplasia, or treatment-related AML or any chronic medical or psychologic illness (such as active infection, chronic active hepatitis, ejection fraction < 50%, diffusion capacity of carbon monoxide [DLCO] < 50%, or creatinine clearance < 60 mL/min) that in the judgment of the physician would jeopardize the ability of the patient to tolerate aggressive chemotherapy.

This clinical protocol was approved by the institutional review board at the City of Hope National Medical Center. Toxicity grading was performed according to the National Cancer Institute Common Toxicity Criteria. Patient demographic data and disease characteristics are listed in Table 1.

Treatment Plan
All patients received either standard or HD ARA-C–based induction regimens before the treatment plan outlined in Fig 1. All patients received consolidation chemotherapy with HD ARA-C 3 g/m² every 12 hours for eight doses (patients aged 55 to 60 years received 2 g/m²) and idarubicin 12 mg/m² on days 1, 2, and 3. ARA-C doses were modified if creatinine increased during treatment,³⁶ or they were withheld for any signs of cerebellar toxicity or creatinine more than 2.0. After hematopoietic recovery, peripheral stem cells primed with granulocyte colony-stimulating factor were collected with the goal of collecting more than 2 x 10⁶ CD34 cells/kg. The pretransplantation conditioning regimen consisted of fractionated total body irradiation delivered in 10 fractions of 1.2 Gy from day -8 through day -5 for a total dose of 12 Gy. The lungs were blocked to 50% of the dose, and the chest wall received a boost of 6 Gy with an electron beam. On day -4, etoposide (VP16) 60 mg/kg (adjusted ideal body weight) was administered intravenously as previously described,³⁷ followed by cyclophosphamide 75 mg/kg (ideal body weight) administered intravenously over 2 hours on day -2. Mesna 30 mg/kg (ideal body weight) was given on day -2 along with cyclophosphamide. Primed peripheral stem cells were reinfused on day 0.

View larger version (21K): [in this window] [in a new window]   Fig 1. Treatment schema.

Peripheral Stem-Cell Collection and Processing
Stem-cell harvesting and cryopreservation were performed according to institutional protocol.³⁸

Supportive Care
Patients were housed in single rooms with a HEPA filtration system during both consolidation and transplantation. Gut decontamination was accomplished with oral levofloxacin, oral trimethoprim-sulfamethoxazole, and a strict low-bacteria diet, all starting on day -9 of the transplantation regimen. Broad-spectrum antibiotics were used for febrile episodes, and all patients received prophylactic low-dose amphotericin (0.15 mg/kg)³⁹ or itraconazole on completion of chemotherapy or day +1 after stem-cell infusion.

All blood products were irradiated with 25 Gy before infusion. All patients received G-CSF 5 µk/kg/d starting on day +1 after peripheral-blood stem-cell transplantation until an ANC of more than 500 µ/L for 3 consecutive days was achieved.

IL-2 Therapy
Intravenous fluids with normal saline were infused at 500 mL/m²/24 h. Patients received prophylactic levofloxacin to prevent bacterial infections during IL-2 induction and maintenance. All patients received acetaminophen, diphenhydramine, and indomethacin before IL-2 was started and indomethacin was continued throughout the initial 4 days of IL-2.

Statistical Methods
Comparisons between strata such as cytogenetic grouping or FAB type were tested using Fisher’s exact test⁴⁰ for discrete frequencies and the Wilcoxon rank sum test⁴¹ for continuous measurements. Tests were two-sided, and the cutoff for statistical significance was .05. Relapse and DFS were calculated from time of consolidation treatment for the intent-to-treat and transplantation analyses. Kaplan-Meier⁴² survival estimates were tested using the Mantel-Haenszel⁴³ (log-rank) test. The 95% confidence intervals (95% CI) on the Kaplan-Meier estimates were calculated using a logit transformation of Greenwood’s estimate of the variance.⁴⁴ Factors possibly associated with relapse and DFS were examined by univariate Cox regression analysis.⁴⁵ Variables tested for statistical significance were age at diagnosis, WBC count at diagnosis, cytogenetics, FAB type, whether induction therapy consisted of standard dose ARA-C versus HD ARA-C, time from CR to autologous BMT, and the number of courses of induction chemotherapy to enter CR. Predictors significant at P < .20 were entered as candidate variables into the stepwise algorithms. Risk ratios were reported with 95% CI.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Fifty-six adult patients with de novo AML in first remission were entered on study with the intent to proceed to ASCT (Table 1).

HD ARA-C and Idarubicin Consolidation
All 56 patients underwent consolidation chemotherapy with HD ARA-C and idarubicin as outlined in Fig 1. Median time from CR to start of HD ARA-C consolidation therapy was 33.5 days (range, 8 to 98 days). Two patients (4%) experienced a delay of greater than 3 months. Patients achieved an ANC of greater than 500/µL at a median of 26 days (range, 17 to 62 days), an ANC of greater than 1,000/µL at a median of 27 days (range, 18 to 65 days), and an untransfused platelet count of greater than 20,000/µL at a median of 37 days (range, 19 to 126 days). Two patients developed cerebellar toxicity; one patient recovered and proceeded to ASCT, and one patient relapsed and did not receive ASCT.

Nine patients (16%) did not proceed to ASCT. One death attributable to neutropenic sepsis occurred during consolidation. Four patients (7%) developed prohibitive toxicity from consolidation (one each for demyelinating neuropathy, severe Clostridium difficile infection and neutropenic colitis, atrial fibrillation with ejection fraction of 42%, and persistent thrombocytopenia after stem-cell collection). Of these four patients, three remain in remission. Four patients (7%) relapsed before ASCT; two patients died in relapse, one patient was transplanted with primed stem cells collected while in remission, and one patient received salvage chemotherapy and is currently in remission.

Stem-Cell Collection and ASCT
The median interval from initiation of consolidation to start of stem-cell collection was 31 days (range, 23 to 114 days). A median number of four stem-cell aliquots (range, 1 to 16) of 3.52 x 10⁶ CD34 cells (range, 1.1 to 20.95) were collected. One patient required bone marrow to be collected and reinfused because only 1.1 x 10⁶ CD34 cells/kg could be collected. No patients received less than 2 x 10⁶ CD34 cells/kg.

Forty-seven patients underwent ASCT at a median time of 3.68 months (range, 2.33 to 10 months) from CR, with 13% of patients receiving ASCT more than 6 months after CR. Delays were attributed to protracted hematopoietic recovery post-HD ARA-C and idarubicin consolidation. Patients achieved an ANC of greater than 500/µL at a median of 10 days (range, 8 to 22 days), an ANC of greater than 1,000/µL at a median of 11 days (range, 9 to 33 days), an untransfused platelet count of greater than 20,000/µL at a median of 22 days (range, 7 to 183 days), and an untransfused platelet count of greater than 50,000/µL at a median of 36 days (range, 12 to 320 days), excluding patients who relapsed or died. The delay in platelet recovery (> 50,000/µL) in the ASCT patients reflects the thrombocytopenic effect of IL-2 given early after engraftment. Nevertheless, no patient had graft failure as a consequence of this, and all have achieved hematopoietic recovery. Mucositis requiring parenteral nutrition and narcotics was observed in all ASCT patients. One ASCT patient died of sepsis during the first 30 days, and two patients developed and recovered from interstitial pneumonia (idiopathic and cytomegalovirus, respectively).

IL-2 Therapy
Thirty-nine patients were treated with IL-2 after ASCT (four refusals; one patient had no central venous catheter); one death and two cases of interstitial pneumonia (one cytomegalovirus, one idiopathic) occurred after ASCT. The median time from ASCT to start of IL-2 treatment was 37 days (range, 22 to 75 days). During induction IL-2 treatment, the median (range) decrease in WBC, hemoglobin, and platelets were -1.4 K/µL (-3.8 to 0.7), -1.1 G/dL (-3.9 to 0.5), and -22 K/µL (-51 to 28), respectively. Thirty-four patients received maintenance IL-2 (two refusals; one patient experienced persistent thrombocytopenia, one had no central venous catheter, and one experienced fever and reversible hypotension before starting maintenance IL-2). During IL-2 maintenance therapy, the median (range) change in WBC, hemoglobin, and platelets were 0.6 K/µL (-0.8 to 4.5), 0.2 G/dL (-2 to 7.2), and 12 K/µL (-9 to 44), respectively.

During IL-2 therapy, most patients developed some degree of capillary leak syndrome with mild weight gain. Grade 3 and 4 toxicity included fever (three patients), nausea (one patient), and hypotension (two patients). No patients required care in the intensive care unit for treatment of these complications.

DFS and Overall Survival
With a median follow-up duration of 39.4 months (range, 1.2 to 76.3 months) for all patients and 50.7 months (range, 12.8 to 76.3 months) for survivors, the 2-year cumulative probability of DFS is 68% (95% CI, 55% to 80%) for all 56 patients who intended to undergo ASCT and 74% (95% CI, 62% to 87%) for the 47 patients who underwent ASCT. The probability of relapse is 30% (95% CI, 17% to 42%) and 24% (95% CI, 12% to 36%) for the intent-to-treat group (Fig 2) and ASCT group, respectively. The median time to relapse after CR and ASCT has not been reached. Of the 11 patients who relapsed after ASCT, all have died with persistent disease.

View larger version (14K): [in this window] [in a new window]   Fig 2. Disease-free survival and time to relapse for intent to treat with autologous stem-cell transplant (N = 56).

View larger version (13K): [in this window] [in a new window]   Fig 3. Disease-free survival and time to relapse for interleukin-2-treated patients (N = 39).

View larger version (14K): [in this window] [in a new window]   Fig 4. Disease-free survival for intent to treat with autologous stem-cell transplant on the basis of cytogenetics (N = 56).

View larger version (14K): [in this window] [in a new window]   Fig 5. Disease-free survival for interleukin-2-treated patients on the basis of cytogenetics (N = 39).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We conducted this intent-to-treat study to determine whether IL-2 immunotherapy could be delivered safely and expeditiously after dose-intensive therapy (combining HD ARA-C and idarubicin consolidated for in vivo purging followed by ASCT) and to determine whether this approach would decrease leukemic relapse, which remains the major cause of failure after autologous transplantation for AML.^46–51 In an attempt to diminish questions of selection bias, which are often raised in ASCT studies, patients were enrolled on the study after achieving a remission and before receiving any consolidation therapy. In this study, most patients were enrolled on the study within 34 days of achieving CR and received ASCT within 3.7 months of achieving a remission.

In an attempt to decrease the relapse rate before ASCT and to improve in vivo purging chemotherapy, most investigators use a single consolidation cycle that is based on HD ARA-C. The Medical Research Council AML trial⁵² used amsacrine, cytarabine, and etoposide before bone marrow harvest and an additional cycle of cytarabine and mitoxantrone after bone marrow harvest and before autologous bone marrow transplantation (ABMT). Six percent of their patients died from infection while hypoplastic from the latter course of chemotherapy. In this study, we used a single cycle of HD ARA-C and idarubicin before stem-cell collection; four patients (7%) relapsed before ASCT, one patient (2%) died as a result of toxicity, and four patients were unable to proceed to ASCT as a result of regimen-related toxicity. Eighty-four percent of patients proceeded to ASCT, which compares favorably with other ASCT studies. The relapse rate is comparable to the Linker et al⁵³ study using HD ARA-C and etoposide, which had a relapse rate of 8%, and a study using only HD ARA-C for consolidation, in which 12% of patients relapsed before ABMT.⁴⁶ The exact number of consolidation cycles required for optimal in vivo purging before ASCT remains to be defined.

Gene-marking studies have shown that reinfusion of clonogenic tumor cells can contribute to relapse after ABMT.²¹ Residual leukemia in patients also contributes to relapse, as demonstrated by the high relapse rate in patients who receive syngeneic transplants.²⁰ Relapse of AML after ASCT tends to occur within the first year. Because IL-2–responsive lymphocytes have been detected in the circulation within 2 or 3 weeks after autologous transplantation, we explored the use of IL-2 early after engraftment to treat minimal residual disease remaining in the patient after conditioning or after having been reinfused with the stem-cell graft. The schedule of IL-2 used in this study was derived from phase I studies that demonstrated an increase in the number of CD8⁺ T cells and CD16⁺, CD56⁺-activated natural-killer cells after IL-2 is stopped; these cells exhibited enhanced cytotoxicity against in vitro tumor targets.³¹ In this trial, we were successfully able to administer IL-2 with little toxicity to 68% of patients at a median of 37 days after stem-cell reinfusion.

In the present study, 2-year projected DFS and relapse rates for the 56 intent-to-treat patients are 68% (95% CI, 55% to 80%) and 30% (95% CI, 17% to 42%), respectively; the rates are 74% (95% CI, 62% to 87%) and 24% (95% CI, 12% to 36%), respectively, for the 47 ASCT patients. In our previous study using the same conditioning regimen without IL-2, the projected 2-year DFS and relapse rates for the intent-to-treat group were 49% (95% CI, 37% to 62%) and 44% (95% CI, 31% to 58%), respectively, and 61% (95% CI, 46% to 74%) and 33% (95% CI, 20% to 49%), respectively, for the ABMT patients.⁴⁶ Given that this is a historical comparison, the role of posttransplant IL-2 in a randomized trial comparing ABMT with or without posttransplant IL-2 would be required to define the efficacy of IL-2 in preventing relapse in each of the cytogenetic risk groups.

Trials with immunotherapy after autologous transplantation have used varying regimens and routes of administration of IL-2 as well as cyclosporine and Linomide in an attempt to generate cytotoxic effector cells with antileukemic activity. A randomized study comparing Linomide with placebo after ASCT showed no benefit in the Linomide-treated group and failed to show enhancement of natural-killer cells in the regenerating bone marrow.⁵⁴ Cyclosporine used after ASCT to induce autologous graft versus host disease has not demonstrated a survival advantage in those patients developing graft versus host disease.^55–57 Varying schedules of IL-2 have had mixed results in the postautologous transplantation setting. A phase I/II trial that used the same IL-2 regimen as this study demonstrated a 25% disease-free plateau for patients transplanted for AML beyond CR1.³¹ In a recent study in Seattle, 10 of 17 (59%) AML patients beyond CR1 treated by ABMT with posttransplant IL-2 remain in CR.⁵⁸ Using sequential IL-2 over a period of 2 months after ABMT, Blaise et al⁵⁹ reported 3-year relapse probabilities of 59% ± 11% for 22 AML patients in CR1; these results did not differ from those obtained without postgraft immunotherapy. Schiller et al⁶⁰ assessed the role of IL-2–mobilized peripheral stem cells and found no difference in leukemia-free survival when compared with matched historical controls. Although these results suggest that IL-2 after transplantation may be the most promising of current immunostimulatory modalities, the outcomes are highly schedule dependent and must be linked to effective pretransplant cytoreduction to achieve maximum effect.

Our data provide evidence for a safe and efficacious approach of administering IL-2 early after a radiation-based regimen and primed peripheral stem cells, collected after a single consolidation cycle with HD ARA-C and idarubicin. This trial provides a reference for further investigation of immunotherapy after ASCT using a combination of cytokines and vaccination, and ultimately the development of specific cytotoxic cells against specific targets on AML cells.

	ACKNOWLEDGMENTS

 
We acknowledge the dedication of nurses at the City of Hope to the care of patients on this study. We thank Diana Garcia for assistance in manuscript preparation; Doni Woo, Kim Gilfillan, and Trudy Trimmer for data collection assistance; and the staff of Information Sciences for data management.

	NOTES

 
Supported by grant nos. CA 30206 and CA 33572 from the National Cancer Institute.

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Submitted December 26, 2001; accepted October 25, 2002.

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