key: cord-0005640-vhpzdnbp
authors: Robinson, N; Benyunes, MC; Thompson, JA; York, A; Petersdorf, S; Press, O; Lindgren, C; Chauncey, T; Buckner, CD; Bensinger, WI; Appelbaum, FR; Fefer, A
title: Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study
date: 1997-12-18
journal: Bone Marrow Transplant
DOI: 10.1038/sj.bmt.1700687
sha: 95004cd43f731cf90a3b02353eb1ff77fc2e5784
doc_id: 5640
cord_uid: vhpzdnbp

The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of ‘induction’ IL-2 of 9, 10, or 12 × 10(6) IU/m(2)/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 × 10(6) IU/m(2)/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 × 10(6) IU/m(2)/day × 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.

Characteristics of patients in the phase I trial (n = 15)

Acetaminophen, indomethacin, diphenhydramine, meperi-

dine and furosemide were administered as clinically indicated. All but the first seven patients received prophylactic antibiotics -vancomycin and ciprofloxacin for adults, van-Sex 6 M/9 F comycin and ceftazidime followed by a broad-spectrum Diagnosis NHL 7 oral antibacterial drug for children. MM 

Immunologic studies AML 1 Immunophenotyping of peripheral blood mononuclear cells

Conditioning regimen a (PBMC) was performed by standard methods. 16 The per-

centage of CD56 'bright' and 'dim' cells was measured C 3 when the staining intensity led to clearly defined boundaries D 2 within the population of CD56 + PBMC. Lymphokine-acti-Stem cell source vated killer effector (LAKe) activity was assessed by the BM 7 ability of PBMC to lyse the natural killer (NK)-resistant PB 5 Daudi cell line in a 4 h 51 Cr-release assay without exposure BM/PB 3 to IL-2 in vitro. 16 

fied TBI (9 Gy). 13 Student's t-test was used to compare hematologic parameters, LAKe activity, and absolute number and percentages of lymphocytes expressing particular phenotypic determinants as a function of IL-2 therapy. Statistics on relapse were calculated by the method of Kaplan and renal toxicity. All protocols and consent forms were Meier. 17 approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center or the University of Washington Medical Center.

Determination of the MTD: All 15 patients on the dose-Therapy with recombinant IL-2 (aldesleukin; Chiron Corescalation phase I portion of the study were evaluable for poration, Emeryville, CA, USA) began a median of 46 toxicity. Dose-limiting toxicities were seen in patients at (range 23-204) days after ASCT. Fifty-six of 67 patients induction levels II-IV. At induction level II, the highest (84%) began IL-2 therapy before day 100. In the phase I daily dose level, dose-limiting toxicities were hallucistudy, cohorts of three to four patients (total 15) received nations in one patient, Gram-negative sepsis which was escalating dose levels of induction IL-2 consisting of 9, 10, fatal in one patient 25 days after completion of IL-2 theror 12 × 10 6 IU/m 2 /day by continuous i.v. (CIV) infusion for apy, and non-fatal bacteremia in two other patients. None 4 or 5 days as inpatients (Table 3) . After 4 days of rest, of the three infected patients had received prophylactic antiall patients received 1.6 × 10 6 IU/m 2 /day of maintenance biotics. All subsequent patients received prophylactic anti-IL-2 by CIV infusion for 10 days via a portable infusion biotics. At level III, dose limiting toxicities were stomatitis pump as outpatients. In the subsequent phase II study, 52 (one) and nausea with intractable hiccups (one). At level additional patients received the previously determined IV, three patients had dose-limiting toxicities. One patient, maximum tolerated dose (MTD) of induction IL-2, folwho had received BCNU as part of her conditioning regilowed by the same maintenance IL-2 regimen. men, developed fatal ARDS after maintenance IL-2. Auto-Toxicity was graded according to WHO criteria. If a psy showed diffuse alveolar damage that was attributed to patient developed grade IV toxicity (or grade III neurologic BCNU. One patient was diagnosed with parainfluenza III or cardiac toxicity), IL-2 was stopped and not resumed. If virus pneumonia by bronchoalveolar lavage on day 3 of a patient developed grade III toxicity (or grade II neuromaintenance IL-2. IL-2 was stopped and the patient recologic or cardiac toxicity), IL-2 therapy was discontinued vered. A third patient developed self-limited stomatitis. until return to baseline or grade I toxicity at which time Level I was associated with no significant toxicities and IL-2 therapy was resumed at 50% of the initial dose. If was determined to be the MTD. grade III toxicity recurred, IL-2 was stopped and not resumed. The MTD was defined as one dose level below the dose level at which three out of a maximum of six Clinical outcome: Of the seven patients with NHL, two patients treated at dose levels above the MTD died of the patients developed уgrade III toxicity. Table 3 Induction dose escalation scheme for the phase I trial Table 4 Induction and maintenance IL-2 toxicities in the phase II trial developed bacteremia -four with coagulase-negative Staphylococcal species and one with JK diphtheroideswhich resolved. Two AML patients died of pulmonary complications after completing induction IL-2: one patient biotics during the rest period, Gram-negative. Grade 3 pulmonary toxicity was seen in an infant with a history of with a prior history of HD treated with mantle radiation died of ARDS, and one died of CMV pneumonia 53 days intermittent collapse of the right upper lobe of the lung due to pre-transplant RSV bronchiolitis. She presented on the after ASCT. The median length of stay in hospital for IL-2 therapy was 6 (range 2-37) days.

last day of maintenance IL-2 with tachypnea. This partially improved with oxygen and diuretic therapy, but definitive Ten patients received no maintenance therapy. Of these, five had had serious toxicity as described above (BOOP, diagnosis of the pulmonary process was never made as she was found to have leukemic relapse in her bone marrow. ARDS, CMV pneumonia, desquamation, bacteremia), four refused and one was found to have CMV antigenemia and CMV in the urine from a sample collected prior to begin-Dose delivery: Forty-one of the 52 patients (79%) received the complete IL-2 induction dose and 91% of the patients ning induction IL-2. That patient completed induction IL-2, did not receive maintenance IL-2, received gancyclovir received у75% of the planned dose. Failure to receive the full IL-2 dose was due to refusal (three), capillary leak syn-and never developed CMV disease.

Forty-two patients received maintenance therapy. The drome (three), hypotension (one), bacteremia (one), elevated aspartate aminotransferase (AST; one), BOOP (one) clinical toxicities observed are listed in Table 4 . The most common symptoms were fatigue and malaise, which were and pharmacy error (one).

Of the 42 patients who received maintenance IL-2, 28 cumulative and peaked toward the end of the maintenance infusion. Six patients developed hypotension with anorexia (67%) received the full dose, 84% received у75% of the dose and 16% received Ͻ75% of the dose. Decreased dose and responded to IV fluids. Fever у grade 2 occurred in 10 patients. Four patients had bacteremia -three Gram-delivery was due to refusal (three), nausea (two), bacteremia (three), fever (two), C. difficile diarrhea (one), anti-positive, and one, in a patient who had not received anti-biotic therapy for a prior bacteremia (one) and pharmacy error (one).

Hematologic effects: The hematologic effects of IL-2 therapy are shown in Figure 1 . Lymphocyte, neutrophil and eosinophil counts rose during IL-2 therapy in the majority of patients. One patient developed transient unexplained neutropenia during maintenance IL-2 therapy. All patients developed thrombocytopenia during induction IL-2, with a nadir 24 h after finishing induction IL-2. The platelet count fell to р20 000/mm 3 in 21 patients whose median pre-IL-2 platelet count had been 40 000/mm 3 (range 17 000-103 000). The remainder of the patients, whose median platelet count had been 118 000/mm 3 (range 49 000-263 000), did not drop their platelet count below 20 000/mm 3 . Platelet counts rose during maintenance IL-2 in all patients, and totally recovered by the end of maintenance therapy.

Other laboratory abnormalities: During induction IL-2, patients developed mild elevations in serum bilirubin (peak 0.2-6.0 mg/dl, median 1.2) and creatinine (peak 0.5-3.6 mg/dl, median 1.0). One patient developed an elevated AST patients tested before IL-2, 24 h after induction IL-2, and 24 h after maintenance IL-2.

Immunomodulatory effects of dose level I: Lymphocytosis was observed after induction IL-2. It reflected a rise in the number of cells expressing CD3, CD4, CD8, CD56 and p75 Patient outcome: The clinical outcomes for the phase II trial are summarized in Table 2 . Fourteen of 24 NHL ( Figure 2 ). Cells expressing CD56, CD8 and p75 remained elevated at the end of maintenance therapy. The increase patients remain in CR a median of 20+ months (range 12+ to 37+) after ASCT. Of the six patients with HD, four in CD56 + lymphocytes represented an expansion of both CD56 'bright' and 'dim' cells (data not shown).

relapsed while two remain in CR at 18+ and 20+ months.

Of the three patients with MM, one developed new bony Before IL-2 therapy, cells from six of 22 patients exhibited mild LAK effector activity, with 10-19% lysis of lesions at 13 months and two, both with a PR after ASCT (defined as 75% or greater reduction in serum or urine Daudi. After induction IL-2, significant LAK effector activity was detected in PBMC from all 18 patients tested monoclonal protein with absence of progression of bony disease), have not progressed at 21+ and 25+ months. (without IL-2 in vitro), with a median of 35.6% lysis (range 11-98%; P у 0.0005 vs pre-IL-2 therapy). After mainte-Of the 16 patients with AML, two died due to treatment, one died in CR 7 months after ASCT with idiopathic car-nance IL-2, LAKe activity (82% lysis) was noted in cells from one of four patients tested.

diac fibrosis, nine relapsed -including one who had relapsed cytogenetically before IL-2 therapy was initiatedand four remain in CR 12+ to 25+ months after ASCT. The three patients with ALL remain in CR at 15+ to 25+ months.

Relapse remains the major limitation of ASCT for hematologic malignancy. [1] [2] [3] [4] Intensification of transplant conditioning regimens has not substantially reduced the problem. 18 It is hypothesized that IL-2 administered early after transplantation might eradicate residual tumor cells, thereby reducing the relapse rate. The basis for this hypothesis is the following: (1) lymphocytes stimulated by IL-2 in vitro responses -including durable complete remissions -in patients with AML, malignant lymphoma and multiple ing IL-2 treatment, with a concurrent increase in the ability of the cells to kill NK-resistant tumor targets without myeloma refractory to conventional therapy; 5,6,8,9 (5) IL-2 is more likely to be effective against minimal residual dis-exposure to IL-2 in vitro. Moreover, the percentage and absolute number of circulating lymphocytes which ease, a setting which can be achieved by current transplant conditioning regimens; and (6) IL-2 after ASCT can induce expressed p75 also increased significantly after IL-2 therapy. This ␤ subunit of the IL-2 receptor binds IL-2 with a syndrome consistent with GVHD, 21 and, therefore, might induce a GVL effect.

intermediate affinity. NK cells constitutively express p75 and, therefore, can immediately respond to IL-2, whereas The IL-2 regimen tested in these trials evolved from our experience with solid tumor patients and from earlier stud-resting T cells do not express p75 but, after antigen recognition by the T cell receptor, the T cells express both CD25 ies with ABMT. 11, 12, 22, 23 Moderate doses of IL-2 were given to induce expansion of both T and non-T lymphocytes. A and p75, and can respond to exogenous IL-2. 31 The increase in cells expressing p75 is consistent with the increased short rest period followed to allow recovery from IL-2 toxicities. A low dose of IL-2 was then administered to main-number and proportion of NK cells and of activated T cells in the circulation after ASCT, capable of immediately tain the immunomodulatory effects. IL-2 therapy was begun early after recovery from the toxicities of ASCT, at responding to IL-2. The clinical significance of these immunomodulatory changes, which are consistent with those a time of minimal residual disease and before relapses would be likely to occur.

reported in other trials with moderate doses of IL-2, 10,11,24 remains unknown. The clinical toxicities of induction IL-2 observed in this study were similar to those previously described. 10, 24 In the The phase I and II trials were primarily designed to determine the MTD of this IL-2 regimen and to gain experience phase I portion of the study, the main dose-limiting toxicities included pulmonary toxicity and bacterial infections with its use, in anticipation of phase III trials. 32 The phase II study involved a small and heterogeneous group of (without prophylactic antibiotics). In the phase II trial with the MTD of IL-2, there were two unexpected deaths, while patients and, therefore, permitted no conclusions regarding clinical outcome. the toxicities were otherwise predictable and manageable. Side-effects of induction IL-2 consisted largely of fever and Of the largest subgroup of patients in the phase II study, ie those with NHL, 58% remain in CR with a minimum mild capillary leak. Laboratory abnormalities of liver and kidney function were mild, peaked at the end of induction follow-up of 1 year. These results are encouraging but not conclusive. IL-2, and quickly resolved. Lymphocytosis, neutrophilia, and eosinophilia were common. The latter two have been Of 16 patients treated for AML, there were two nonrelapse deaths attributed to IL-2, nine relapses, and one ascribed to the release of secondary cytokines including GM-CSF and IL-5. 25 death in CR, so that only four remain alive in CR. Overall, the relapse probability, 66%, is similar to that reported There was a 6% mortality rate on this study, 3.5% at the MTD, due to infections and/or pulmonary toxicity. While without IL-2 4 and higher than that reported in our previous study with IL-2. 11,33 However, the regimen and source of all non-relapse causes of morbidity and mortality during or shortly after the IL-2 treatment are ascribed to IL-2, some IL-2 used in this trial was different from that used in the past (Roche in the past, Chiron in the present trial), as was may have been due to the transplant conditioning regimens and/or pre-existing medical conditions. The occurrence of the stem cell source (only marrow in past trials vs largely PB or PB plus BM in the present trial). The possibility that CMV pneumonia in one of 67 patients treated with IL-2 is no different from the rate seen in non-IL-2-treated ASCT relapses of AML might be more frequent after PBSC than after marrow transplant, as raised by some reports, 34,35 patients. 26,27 A high incidence of bacterial infections, ascribed to an acquired defect in neutrophil chemotaxis in might also explain the discrepant results. However, the patient groups in the various trials were small, hetero-IL-2-treated patients, 28 has been reported in patients receiving IL-2 after BMT. 29 The serious bacterial infections in geneous, and not necessarily clinically comparable.

Our clinical results in a very small number of patients this study occurred largely in patients who had not received prophylactic antibiotics. The incidence of bacteremia was with HD, MM, and ALL, although encouraging, are necessarily uninterpretable. Although some promising results significantly reduced by prophylactic antibiotics (from 3/7 to 9/60 patients).

have been reported with IL-2 without ASCT in HD 8, 36 and in MM, 9 one regimen of IL-2 given after ASCT for ALL Four patients developed major non-infectious pulmonary toxicities. Although all four had a history of pulmonary in a randomized trial did not reduce the relapse rate. 1 The IL-2 regimen identified in the phase I trial and insult -BCNU therapy, RUL collapse due to RSV bronchiolitis, BOOP and mantle radiation for HD -it is explored in the phase II trial is now being tested in two SWOG phase III trials of IL-2 after ASCT for AML and not known whether these predisposed or contributed to the toxicities attributed to IL-2.

NHL. The results will determine whether consolidative immunotherapy with IL-2 administered after ASCT will Circulating IL-2-responsive cells that can mediate LAK activity in vitro are usually detectable as early as 2 weeks decrease the relapse rates and improve disease-free and overall survival of such patients. after ASCT. 16, 20, 30 In the phase II trial, IL-2 induced a lymphocytosis which reflected an increase in cells of the cytotoxic T cell phenotype (CD8 + ) and of the activated NK Acknowledgements phenotype (CD56 + ). Both CD56 + 'bright' cells, representing proliferating NK cells, and CD56 + 'dim' cells, 

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