Leukemia & Lymphoma
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Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia Sylvain P. Chantepie, Emilie Reboursiere, Jean-Baptiste Mear, Anne-Claire Gac, Veronique Salaun, Khaled Benabed, Stéphane Cheze, Hyacinthe Johnsonansah, Margaret Macro, Jean-Pierre Vilque & Oumedaly Reman To cite this article: Sylvain P. Chantepie, Emilie Reboursiere, Jean-Baptiste Mear, Anne-Claire Gac, Veronique Salaun, Khaled Benabed, Stéphane Cheze, Hyacinthe Johnsonansah, Margaret Macro, Jean-Pierre Vilque & Oumedaly Reman (2015) Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia, Leukemia & Lymphoma, 56:8, 2326-2330, DOI: 10.3109/10428194.2014.986478 To link to this article: http://dx.doi.org/10.3109/10428194.2014.986478
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Leukemia & Lymphoma, August 2015; 56(8): 2326–2330 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.986478
ORIGINAL ARTICLE: CLINICAL
Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia Sylvain P. Chantepie1, Emilie Reboursiere1, Jean-Baptiste Mear1, Anne-Claire Gac1, Veronique Salaun2, Khaled Benabed1, Stéphane Cheze1, Hyacinthe Johnsonansah1, Margaret Macro1, Jean-Pierre Vilque3 & Oumedaly Reman1 1Department of Hematology and 2Hematology Laboratory, Caen Teaching Hospital, Caen, France and
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3Department of Hematology, François Baclesse Cancer Center, Caen, France
tion of 9 mg/m2 on day 1 and on day 14 induced a response rate of 26% (13% CR and 13% CR with incomplete platelet recovery [CRp]) with median survival of 4.9 months [5]. Several studies have evaluated GO in combination with various agents in relapsed or refractory AML [6–18]. The response rate ranges from 12 to 63% with a median survival of 2–9.5 months. However, in these studies, GO was administered in one or two doses of 3–9.0 mg/m2. Recent studies have used fractionated GO (fGO) to reduce toxicity and increase efficacy (GO 3 mg/m2 on days 1, 4 and 7). GO, without intensive chemotherapy (ICT), produced 33% CR with survival of 8.4 months [19]. CR rates ranged from 55 to 80% for GO with ICT [3,20,21] or GO with cytarabine [22]. The median survival was 15, 19.8, 35 and 34 months, respectively. However, two of these four studies investigated efficacy in patients with relapsed AML with a CR1 duration of 6 months [20,22], and the two remaining studies included only 30% and 33% of patients with AML with a CR duration of ⬍ 6 months [3,21]. The purpose of this study was to investigate the efficacy and toxicity of GO with ICT in all patients with relapsed or refractory CD33-positive AML, regardless of CR1 duration.
Abstract The prognosis of refractory/relapsed acute myeloid leukemia (AML) remains poor. The complete response (CR) rate after relapse is around 25%, with 11% of patients still alive after 5 years. The efficacy and toxicity of fractionated gemtuzumab ozogamicin (fGO; 3 mg/m2, days 1, 4, 7) in combination with intensive chemotherapy were retrospectively evaluated in patients with refractory/relapsed AML. Thirty-six patients (median age 54 years) were included. European LeukemiaNet classification was as follows: favorable (n ⴝ 6), intermediate-I (n ⴝ 13), intermediateII (n ⴝ 8), adverse (n ⴝ 9). Median CR duration was 7.16 months (1.63–96.8). The overall response rate was 38.8%, with CR in eight patients (22.2%) and CR with incomplete platelet recovery (CRp) in six patients (16.7%). Two-year overall survival was 26% (95% confidence interval [CI]: 12–42) and 2-year relapse free-survival was 18.5% (95% CI: 6.6–35.0). Salvage therapy with fractionated GO in patients with very high-risk disease produced a 38.8% response rate and may be considered as a bridge therapy to transplant. Keywords: Myeloid leukemias and dysplasias, chemotherapeutic approaches, clinical results
Introduction
Methods
The prognosis for patients with refractory or relapsed acute myeloid leukemia (AML) remains poor. The complete response (CR) rate after relapse is around 25–50%, with 11% of patients still alive after 5 years [1–3]. The median duration of second CR (CR2) is often shorter than that of CR1. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody attached to calicheamicin. GO induces cell death in CD33-positive leukemic cells by internalization of the calicheamicin drug and cleavage of double-stranded DNA [4]. In patients with relapsed AML, a single GO injec-
Eligibility criteria All patients treated with GO and chemotherapy at Caen Teaching Hospital or Baclesse Cancer Center were included in the study. Patients were classified according to the prognostic index for relapse developed by Breems et al. [1]. Patients were considered eligible for salvage with GO if they had a World Health Organization (WHO) performance status ⱕ 2, and adequate hepatic and renal function as defined by: total bilirubin ⱕ 1.5 mg/dL, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic
Correspondence: Dr. Sylvain P. Chantepie, MD, University Hospital, Hematology, Cote de Nacre Avenue, France, 14000 France. E-mail: [email protected] Received 8 August 2014; revised 24 October 2014; accepted 7 November 2014
2326
GO in relapsed/refractory AML 2327 pyruvic transaminase (SGPT) ⱕ 2.5 ⫻ upper limit of normal (ULN), creatinine ⱕ 1.5 mg/dL or calculated creatinine clearance ⱖ 50 mL/min.
Immunophenotyping, cytogenetics and molecular analysis Immunophenotyping was performed in the same laboratory. CD33 expression was determined by dividing the mean fluorescence intensity of CD33 on leukemic blasts by the mean fluorescence intensity of its isotype control. A ratio of ⱖ 2 was considered positive, as previously described [23]. Patients were classified according to their standardized cytogenetic and molecular risk subgroups [24].
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Salvage regimen Salvage therapy involved GO 3 mg/m2 (maximum dose 5 mg) on days 1, 4 and 7 with cytarabine 200 mg/m2 on day 1 to day 7, with or without anthracycline on days 1–3 or the FLAG-Ida regimen (fludarabine, cytarabine, granulocyte colony stimulating factor [G-CSF], idarubicin). All patients were treated in a laminar air-flow isolation room. In the case of CR, consolidation therapy with chemotherapy and GO 3 mg/m2 (maximum dose 5 mg) was administered on day 1. Patients in remission and eligible for hematopoietic stem cell transplant (HSCT) received an allogeneic graft if a donor was available. Patients were considered eligible for allogeneic stem cell transplant in the case of chemosensitivity after GO salvage therapy, WHO performance status ⱕ 2, calculated creatinine clearance ⱖ 50 mL/min, total bilirubin ⱕ 1.5 mg/dL, SGOT and SGPT ⱕ 2.5 ⫻ ULN, forced expiratory volume (FEV) ⬎ 50% and left ventricular ejection fraction ⬎ 50%.
Response criteria CR was defined by ⱕ 5% blasts in the bone marrow with more than 1 ⫻ 109/L neutrophils and 100 ⫻ 109/L platelets in peripheral blood. CRp was as for CR but with incomplete platelet recovery [25].
Toxicity assessment Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.
Statistical analysis Overall survival (OS) was calculated from the date of the start of therapy until death. Relapse-free survival (RFS) was calculated from the date of initial response to disease recurrence. Event-free survival (EFS) was calculated from the date of the start of therapy until an event, including death, death in induction or relapse, occurred. The patients’ characteristics were compared by means of χ2 test for binary variables and Mann–Whitney test for continuous variables. Kaplan–Meier curves were plotted for survival, and data for the various groups were compared by means of the log-rank test. Multivariate analysis was performed with a Cox model after the proportional hazards assumption was checked. A p-value less than 0.05 was considered to be statistically significant.
Results Patient characteristics A total of 36 patients, median age 54 (range 14–70), received chemotherapy and GO, and their characteristics can be seen in Table I. Patients had refractory disease (n ⫽ 8) or were in first relapse (n ⫽ 28). The duration of first remission was 6 months or less in 42.9% of patients and ⬎ 6 months in 57.1% of patients. The prognostic index for relapse was poor in the majority (67.9%) of patients in relapse (n ⫽ 19), intermediate in 21.4% (n ⫽ 6) and favorable in 10.7% (n ⫽ 3). All had previously received at least one cycle of intensive induction chemotherapy, and one relapsed after HSCT.
Response An overall response was observed in 14 patients (38.8%), including CR in eight patients and CRp in six patients. The response rate was 42.8% in relapsed AML and 25.0% in refractory AML. At 24 months, OS was 26% (95% confidence interval [CI]: 12–42) and RFS was 18.5% (95% CI: 6.6–35.0) (Figures 1 and 2). The median duration of CR2 was 2.8 months (range 0.4–44.4). Median survival was similar between the different European LeukemiaNet (ELN) classification groups and
Table I. Characteristics of patients. Patients (n ⫽ 36) Median age (range) Sex, M/F ELN, n (%) Favorable Intermediate-I Intermediate-II Adverse Relapsed/refractory, n (%) CR1 duration, months, median (range) CR ⬎ 6months, n (%) CR ⱕ 6months, n (%) Prognostic index for relapse [1], n (%) Favorable-risk Intermediate-risk Poor-risk Previous induction chemotherapy, n (%) 3⫹7 Timed sequential* Previous HSCT WBC at salvage therapy, median (range) % CD33 expression, median (range) Ratio intensity of CD33 blasts/control Salvage regimen with GO 3⫹7 FLAG-Ida Cytarabine Death in induction Response rate, n (%) CR CRp CR ⫹ CRp in refractory AML CR ⫹ CRp in relapsed AML HSCT after salvage, n (%)
54 (14–70) 15/21 6 (16.7) 13 (36.1) 8 (22.2) 9 (25.0) 28 (78)/8 (22) 7.16 (1.63–96.8) 16 (57.1) 12 (42.9) 28 3 (10.7) 6 (21.4) 19 (67.9) 36 (100) 26 (72.2) 10 (27.8) 1 (2.7) 4.4 (0.69–231) 95 (30–100) 30.85 (2.3–117) 29 (80.6) 2 (5.6) 5 (13.8) 5 (13.8) 14 (38.8) 8 (22.2) 6 (16.7) 2 (25.0) 12 (42.8) 12 (33.3)
ELN, European LeukemiaNet; CR, complete remission; HSCT, hematopoietic stem cell transplant; WBC, white blood cell count; GO, gemtuzumab ozogamicin; FLAG-Ida, fludarabine, cytarabine, granulocyte colony stimulating factor, idarubicin; CRp, complete remission with incomplete platelet recovery; AML, acute myeloid leukemia. *Daunorubicin 60 mg/m2/day on days 1–3 and 35 mg/m2/day on days 8–9 plus cytarabine 500 mg/m2/day on days 1–3 and 1 g/m2/12 h on days 8–10.
2328 S. P. Chantepie et al. Table II. Characteristics of transplanted group (n ⫽ 12). Patients (n ⫽ 12)
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Figure 1. Probability of overall survival.
between relapsed and refractory groups. The CR rate was 50% in patients with a high CD33 expression ratio compared to 27% in the other group.
Safety Salvage therapy-related mortality at 1 month was observed in five patients: septic shock (n ⫽ 3), cerebral hemorrhage (n ⫽ 1), multiple organ failure (n ⫽ 1) and multifocal leukoencephalopathy (n ⫽ 1). Sinusoidal obstruction syndrome (SOS) was observed in one patient (2.78%) after salvage chemotherapy with GO and was successfully treated before stem cell transplant. Median time to neutrophil recovery (⬎ 500/ mm3) and to platelet recovery (⬎ 20 000/mm3) was 25 and 21 days, respectively. Median red blood cell and platelet transfusions were 7.5 (range 0–22) and 10 (range 4–33), respectively.
Conditioning regimen, n (%) Myeloablative Non-myeloablative Median time from salvage to transplant, months (range) GVHD prophylaxis CSA ⫹ MTX CSA ⫹ MMF Graft source, n (%) MRD PBSC MUD PBSC Haplo PBSC CBU Engraftment, n (%) SOS Remission status before HSCT, n (%) Complete remission Partial response Outcome, n (%) Alive Relapse Death HSCT as cause of death AML as cause of death
6 (50.0) 6 (50.0) 4.8 (2.8–25.2) 6 (50) 6 (50) 1 (8.3) 9 (75) 1 (8.3) 1 (8.3) 12 (100) 0 (0) 10 (83%) 2 (17%) 8 (66.6) 3 (25.0) 4 (33.3) 1 (8.3) 3 (25.0)
GVHD, graft versus host disease; CSA, cyclosporine A; MTX, methotrexate; MMF, mycophenolate mofetil; MRD, match related donor; PBSC, peripheral blood stem cell; MUD, match unrelated donor; Haplo, haplo-identical donor; CBU, cord blood unit; SOS, sinusoidal obstruction syndrome; HSCT, hematopoietic stem cell transplant; AML, acute myeloid leukemia.
patients (fludarabine–busulfan-based conditioning). Two patients received sequential conditioning. No SOS was reported after HSCT. As predicted, OS and RFS in the HSCT group were significantly higher than in the non-HSCT group (Figures 3 and 4, p ⬍ 0.0001 and p ⫽ 0.0002 according to log-rank test).
Prognostic factors Twelve patients (33.3%) received an allogeneic stem cell graft after fGO and salvage chemotherapy. Characteristics are given in Table II. The conditioning regimen was myeloablative in six patients (five patients received busulfan for 4 days with cyclophosphamide for 2 days and one patient received 12 Gy total body irradiation with cyclophosphamide), and non-myeloablative in the six remaining
As shown in Table III, the percentage of blasts in blood, WBC count, performance status and increased SGOT were prognostic factors for OS, but not CD33 expression ratio. The percentage of blasts in blood, performance status, increased SGOT and CD33 expression ratio were prognostic factors for RFS, but not WBC count. Multivariate analysis showed a trend for improved OS and RFS with a good performance status (Table IV).
Figure 2. Probability of relapse-free survival.
Figure 3. Overall survival according to transplant status.
Allogeneic group
GO in relapsed/refractory AML 2329 Table IV. Multivariate analysis.
Prognostic factor Percent blood blasts WBC count Performance status SGOT ⬎ ULN CD33 expression (ratio)
Overall survival, HR, 95% CI, p-value
Relapse-free survival, HR, 95% CI, p-value
1.01 (0.99–1.02), 0.3 1.0 (0.99–1.01), 0.5 1.59 (0.98–2.56), 0.056 1.77 (0.5–5.6), 0.31 –
1.00 (0.99–1.02), 0.34 – 1.44 (0.95–2.18), 0.08 1.92 (0.53–6.9), 0.31 1.01 (0.99–1.02), 0.11
WBC, white blood cell; SGOT, serum glutamic oxaloacetic transaminase; ULN, upper limit of normal; HR, hazard ratio; CI, confidence interval.
Figure 4. Relapse-free survival according to transplant status.
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Discussion This study represents one of the biggest series of fGO with ICT in patients with relapsed or refractory AML (n ⫽ 36). There are very few data on salvage therapy with fGO in patients with very high-risk disease with short CR1 duration (⬍ 6 months) or refractory disease. Publications of studies using fGO in combination with chemotherapy as salvage regimen showed a response rate of 55–80%. However, these studies investigated efficacy in patients with relapsed AML with a CR1 duration of 6 months [20,22], or included a low percentage of 30% and 33% of patients with AML with a CR duration of ⬍ 6 months [3,21]. In the present study, 55% of patients belonged to this high-risk population (22% refractory and 33% CR1 duration ⬍ 6 months) and had a CR rate of 20%. In contrast, patients with CR1 duration ⬎ 6 months had a CR rate of 62.5%, which is very similar to that in the published data. Median RFS and OS after salvage treatment were 2.06 (0.5–44.6) and 2.5 months (0.6–44.6) for the high-risk group, compared to 6.21 (0.4–29.1) and 8.5 months (0.4–34) for the low-risk group with CR1 duration ⬎ 6 months (p ⫽ not significant, log-rank test). In the high-risk population, there is very little chance of achieving CR with standard chemotherapy and consequently of receiving HSCT. However, this study showed an overall response rate (ORR) of 38.8% (CR ⫹ CRp), with 42.8% ORR in relapsed patients and 25.0% ORR in refractory patients. Other salvage regimens without GO reported a CR rate of 11% and 24% in patients with refractory and relapsed AML, respectively [26]. In comparison, another chemotherapy regimen in combination with GO in patients with refractory AML showed a 27% ORR [18]. The addition of fGO to ICT produced promising response rates in a very Table III. Univariate analysis. Prognostic factor Percent blood blasts WBC count Performance status SGOT ⬎ ULN CD33 expression (ratio)
Overall survival, HR, 95% CI, p-value
Relapse-free survival, HR, 95% CI, p-value
1.02 (1.0–1.03), 0.004 1.01 (1.0–1.01), 0.035 1.83 (1.17–2.88), 0.008 3.36 (1.39–8.12), 0.007 NS
1.01 (1.0–1.02), 0.015 NS 1.59 (1.05–2.42), 0.028 3.83 (1.6–9.16), 0.003 1.01 (1.0–1.02), 0.038
WBC, white blood cell; SGOT, serum glutamic oxaloacetic transaminase; ULN, upper limit of normal; HR, hazard ratio; CI, confidence interval; NS, not significant.
high-risk population. However, results must be taken with caution because of the heterogeneity of the chemotherapies used. Although three different ICT regimens were used in combination with GO in the present study, the majority of patients (86.2%) were treated with classic salvage chemotherapy using two or more well-known active drugs in AML. Only 13.8% received cytarabine alone. GO may be combined with different salvage therapies with success. The CD33 expression ratio was also associated with better remission rates and RFS. However, it was not a prognostic factor for OS. The CD33 expression ratio may be a useful tool for more effective screening of patients who may potentially benefit from fGO salvage therapy and achieve a CR, but this must be confirmed in prospective studies. Treatment tolerance is of particular importance in this group of patients previously treated with induction chemotherapy. This study reported induction-related mortality at a rate of 13.8%, which was very similar to treatment-related mortality (18%, 13.8%, 11.1%, 10.4%, 35%, 10%) described with salvage regimens [26–31]. No SOS was reported after allogeneic stem cell transplant in this study. Although the number of patients was relatively small, the use of salvage ICT with fGO does not preclude the subsequent use of allograft. Use of fGO with ICT enabled 12 patients (33%) to receive HSCT, therefore offering a chance of long-term survival. Ten patients were in relapse before salvage treatment and two were refractory. Among the 10 patients in relapse before salvage treatment, according to the Breems classification, one belonged to the low-risk group, four to the intermediate group and five to the high-risk group. Thus, successful salvage treatment and allogeneic stem cell transplant may be offered to all patients, regardless of relapse index group and CR1 duration. The HSCT patient-group showed better survival than patients treated without HSCT. However, the HSCT patient-group included patients with chemosensitive AML, with a clear benefit in terms of survival over non-responders not having received a transplant. To date, there is no standard salvage regimen for patients with refractory or relapsed AML, and many studies have failed to demonstrate the superiority of a given salvage chemotherapy regimen over another. The use of fGO with chemotherapy offers a chance of remission and a possibility of cure with allogeneic stem cell transplant. Despite the limited value due to the small number of patients, this study demonstrated the efficacy and safety of ICT with fGO. HSCT is feasible, without excessive toxicity or SOS.
2330 S. P. Chantepie et al.
Conclusion ICT with fGO induced a 38.8% response rate, offering the possibility of HSCT in 33% of patients. fGO with ICT may be considered in patients with relapsed or very high-risk AML as a bridge to transplant. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia Sylvain P. Chantepie, Emilie Reboursiere, Jean-Baptiste Mear, Anne-Claire Gac, Veronique Salaun, Khaled Benabed, Stéphane Cheze, Hyacinthe Johnsonansah, Margaret Macro, Jean-Pierre Vilque & Oumedaly Reman To cite this article: Sylvain P. Chantepie, Emilie Reboursiere, Jean-Baptiste Mear, Anne-Claire Gac, Veronique Salaun, Khaled Benabed, Stéphane Cheze, Hyacinthe Johnsonansah, Margaret Macro, Jean-Pierre Vilque & Oumedaly Reman (2015) Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia, Leukemia & Lymphoma, 56:8, 2326-2330, DOI: 10.3109/10428194.2014.986478 To link to this article: http://dx.doi.org/10.3109/10428194.2014.986478
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Leukemia & Lymphoma, August 2015; 56(8): 2326–2330 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.986478
ORIGINAL ARTICLE: CLINICAL
Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia Sylvain P. Chantepie1, Emilie Reboursiere1, Jean-Baptiste Mear1, Anne-Claire Gac1, Veronique Salaun2, Khaled Benabed1, Stéphane Cheze1, Hyacinthe Johnsonansah1, Margaret Macro1, Jean-Pierre Vilque3 & Oumedaly Reman1 1Department of Hematology and 2Hematology Laboratory, Caen Teaching Hospital, Caen, France and
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3Department of Hematology, François Baclesse Cancer Center, Caen, France
tion of 9 mg/m2 on day 1 and on day 14 induced a response rate of 26% (13% CR and 13% CR with incomplete platelet recovery [CRp]) with median survival of 4.9 months [5]. Several studies have evaluated GO in combination with various agents in relapsed or refractory AML [6–18]. The response rate ranges from 12 to 63% with a median survival of 2–9.5 months. However, in these studies, GO was administered in one or two doses of 3–9.0 mg/m2. Recent studies have used fractionated GO (fGO) to reduce toxicity and increase efficacy (GO 3 mg/m2 on days 1, 4 and 7). GO, without intensive chemotherapy (ICT), produced 33% CR with survival of 8.4 months [19]. CR rates ranged from 55 to 80% for GO with ICT [3,20,21] or GO with cytarabine [22]. The median survival was 15, 19.8, 35 and 34 months, respectively. However, two of these four studies investigated efficacy in patients with relapsed AML with a CR1 duration of 6 months [20,22], and the two remaining studies included only 30% and 33% of patients with AML with a CR duration of ⬍ 6 months [3,21]. The purpose of this study was to investigate the efficacy and toxicity of GO with ICT in all patients with relapsed or refractory CD33-positive AML, regardless of CR1 duration.
Abstract The prognosis of refractory/relapsed acute myeloid leukemia (AML) remains poor. The complete response (CR) rate after relapse is around 25%, with 11% of patients still alive after 5 years. The efficacy and toxicity of fractionated gemtuzumab ozogamicin (fGO; 3 mg/m2, days 1, 4, 7) in combination with intensive chemotherapy were retrospectively evaluated in patients with refractory/relapsed AML. Thirty-six patients (median age 54 years) were included. European LeukemiaNet classification was as follows: favorable (n ⴝ 6), intermediate-I (n ⴝ 13), intermediateII (n ⴝ 8), adverse (n ⴝ 9). Median CR duration was 7.16 months (1.63–96.8). The overall response rate was 38.8%, with CR in eight patients (22.2%) and CR with incomplete platelet recovery (CRp) in six patients (16.7%). Two-year overall survival was 26% (95% confidence interval [CI]: 12–42) and 2-year relapse free-survival was 18.5% (95% CI: 6.6–35.0). Salvage therapy with fractionated GO in patients with very high-risk disease produced a 38.8% response rate and may be considered as a bridge therapy to transplant. Keywords: Myeloid leukemias and dysplasias, chemotherapeutic approaches, clinical results
Introduction
Methods
The prognosis for patients with refractory or relapsed acute myeloid leukemia (AML) remains poor. The complete response (CR) rate after relapse is around 25–50%, with 11% of patients still alive after 5 years [1–3]. The median duration of second CR (CR2) is often shorter than that of CR1. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody attached to calicheamicin. GO induces cell death in CD33-positive leukemic cells by internalization of the calicheamicin drug and cleavage of double-stranded DNA [4]. In patients with relapsed AML, a single GO injec-
Eligibility criteria All patients treated with GO and chemotherapy at Caen Teaching Hospital or Baclesse Cancer Center were included in the study. Patients were classified according to the prognostic index for relapse developed by Breems et al. [1]. Patients were considered eligible for salvage with GO if they had a World Health Organization (WHO) performance status ⱕ 2, and adequate hepatic and renal function as defined by: total bilirubin ⱕ 1.5 mg/dL, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic
Correspondence: Dr. Sylvain P. Chantepie, MD, University Hospital, Hematology, Cote de Nacre Avenue, France, 14000 France. E-mail: [email protected] Received 8 August 2014; revised 24 October 2014; accepted 7 November 2014
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GO in relapsed/refractory AML 2327 pyruvic transaminase (SGPT) ⱕ 2.5 ⫻ upper limit of normal (ULN), creatinine ⱕ 1.5 mg/dL or calculated creatinine clearance ⱖ 50 mL/min.
Immunophenotyping, cytogenetics and molecular analysis Immunophenotyping was performed in the same laboratory. CD33 expression was determined by dividing the mean fluorescence intensity of CD33 on leukemic blasts by the mean fluorescence intensity of its isotype control. A ratio of ⱖ 2 was considered positive, as previously described [23]. Patients were classified according to their standardized cytogenetic and molecular risk subgroups [24].
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Salvage regimen Salvage therapy involved GO 3 mg/m2 (maximum dose 5 mg) on days 1, 4 and 7 with cytarabine 200 mg/m2 on day 1 to day 7, with or without anthracycline on days 1–3 or the FLAG-Ida regimen (fludarabine, cytarabine, granulocyte colony stimulating factor [G-CSF], idarubicin). All patients were treated in a laminar air-flow isolation room. In the case of CR, consolidation therapy with chemotherapy and GO 3 mg/m2 (maximum dose 5 mg) was administered on day 1. Patients in remission and eligible for hematopoietic stem cell transplant (HSCT) received an allogeneic graft if a donor was available. Patients were considered eligible for allogeneic stem cell transplant in the case of chemosensitivity after GO salvage therapy, WHO performance status ⱕ 2, calculated creatinine clearance ⱖ 50 mL/min, total bilirubin ⱕ 1.5 mg/dL, SGOT and SGPT ⱕ 2.5 ⫻ ULN, forced expiratory volume (FEV) ⬎ 50% and left ventricular ejection fraction ⬎ 50%.
Response criteria CR was defined by ⱕ 5% blasts in the bone marrow with more than 1 ⫻ 109/L neutrophils and 100 ⫻ 109/L platelets in peripheral blood. CRp was as for CR but with incomplete platelet recovery [25].
Toxicity assessment Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.
Statistical analysis Overall survival (OS) was calculated from the date of the start of therapy until death. Relapse-free survival (RFS) was calculated from the date of initial response to disease recurrence. Event-free survival (EFS) was calculated from the date of the start of therapy until an event, including death, death in induction or relapse, occurred. The patients’ characteristics were compared by means of χ2 test for binary variables and Mann–Whitney test for continuous variables. Kaplan–Meier curves were plotted for survival, and data for the various groups were compared by means of the log-rank test. Multivariate analysis was performed with a Cox model after the proportional hazards assumption was checked. A p-value less than 0.05 was considered to be statistically significant.
Results Patient characteristics A total of 36 patients, median age 54 (range 14–70), received chemotherapy and GO, and their characteristics can be seen in Table I. Patients had refractory disease (n ⫽ 8) or were in first relapse (n ⫽ 28). The duration of first remission was 6 months or less in 42.9% of patients and ⬎ 6 months in 57.1% of patients. The prognostic index for relapse was poor in the majority (67.9%) of patients in relapse (n ⫽ 19), intermediate in 21.4% (n ⫽ 6) and favorable in 10.7% (n ⫽ 3). All had previously received at least one cycle of intensive induction chemotherapy, and one relapsed after HSCT.
Response An overall response was observed in 14 patients (38.8%), including CR in eight patients and CRp in six patients. The response rate was 42.8% in relapsed AML and 25.0% in refractory AML. At 24 months, OS was 26% (95% confidence interval [CI]: 12–42) and RFS was 18.5% (95% CI: 6.6–35.0) (Figures 1 and 2). The median duration of CR2 was 2.8 months (range 0.4–44.4). Median survival was similar between the different European LeukemiaNet (ELN) classification groups and
Table I. Characteristics of patients. Patients (n ⫽ 36) Median age (range) Sex, M/F ELN, n (%) Favorable Intermediate-I Intermediate-II Adverse Relapsed/refractory, n (%) CR1 duration, months, median (range) CR ⬎ 6months, n (%) CR ⱕ 6months, n (%) Prognostic index for relapse [1], n (%) Favorable-risk Intermediate-risk Poor-risk Previous induction chemotherapy, n (%) 3⫹7 Timed sequential* Previous HSCT WBC at salvage therapy, median (range) % CD33 expression, median (range) Ratio intensity of CD33 blasts/control Salvage regimen with GO 3⫹7 FLAG-Ida Cytarabine Death in induction Response rate, n (%) CR CRp CR ⫹ CRp in refractory AML CR ⫹ CRp in relapsed AML HSCT after salvage, n (%)
54 (14–70) 15/21 6 (16.7) 13 (36.1) 8 (22.2) 9 (25.0) 28 (78)/8 (22) 7.16 (1.63–96.8) 16 (57.1) 12 (42.9) 28 3 (10.7) 6 (21.4) 19 (67.9) 36 (100) 26 (72.2) 10 (27.8) 1 (2.7) 4.4 (0.69–231) 95 (30–100) 30.85 (2.3–117) 29 (80.6) 2 (5.6) 5 (13.8) 5 (13.8) 14 (38.8) 8 (22.2) 6 (16.7) 2 (25.0) 12 (42.8) 12 (33.3)
ELN, European LeukemiaNet; CR, complete remission; HSCT, hematopoietic stem cell transplant; WBC, white blood cell count; GO, gemtuzumab ozogamicin; FLAG-Ida, fludarabine, cytarabine, granulocyte colony stimulating factor, idarubicin; CRp, complete remission with incomplete platelet recovery; AML, acute myeloid leukemia. *Daunorubicin 60 mg/m2/day on days 1–3 and 35 mg/m2/day on days 8–9 plus cytarabine 500 mg/m2/day on days 1–3 and 1 g/m2/12 h on days 8–10.
2328 S. P. Chantepie et al. Table II. Characteristics of transplanted group (n ⫽ 12). Patients (n ⫽ 12)
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Figure 1. Probability of overall survival.
between relapsed and refractory groups. The CR rate was 50% in patients with a high CD33 expression ratio compared to 27% in the other group.
Safety Salvage therapy-related mortality at 1 month was observed in five patients: septic shock (n ⫽ 3), cerebral hemorrhage (n ⫽ 1), multiple organ failure (n ⫽ 1) and multifocal leukoencephalopathy (n ⫽ 1). Sinusoidal obstruction syndrome (SOS) was observed in one patient (2.78%) after salvage chemotherapy with GO and was successfully treated before stem cell transplant. Median time to neutrophil recovery (⬎ 500/ mm3) and to platelet recovery (⬎ 20 000/mm3) was 25 and 21 days, respectively. Median red blood cell and platelet transfusions were 7.5 (range 0–22) and 10 (range 4–33), respectively.
Conditioning regimen, n (%) Myeloablative Non-myeloablative Median time from salvage to transplant, months (range) GVHD prophylaxis CSA ⫹ MTX CSA ⫹ MMF Graft source, n (%) MRD PBSC MUD PBSC Haplo PBSC CBU Engraftment, n (%) SOS Remission status before HSCT, n (%) Complete remission Partial response Outcome, n (%) Alive Relapse Death HSCT as cause of death AML as cause of death
6 (50.0) 6 (50.0) 4.8 (2.8–25.2) 6 (50) 6 (50) 1 (8.3) 9 (75) 1 (8.3) 1 (8.3) 12 (100) 0 (0) 10 (83%) 2 (17%) 8 (66.6) 3 (25.0) 4 (33.3) 1 (8.3) 3 (25.0)
GVHD, graft versus host disease; CSA, cyclosporine A; MTX, methotrexate; MMF, mycophenolate mofetil; MRD, match related donor; PBSC, peripheral blood stem cell; MUD, match unrelated donor; Haplo, haplo-identical donor; CBU, cord blood unit; SOS, sinusoidal obstruction syndrome; HSCT, hematopoietic stem cell transplant; AML, acute myeloid leukemia.
patients (fludarabine–busulfan-based conditioning). Two patients received sequential conditioning. No SOS was reported after HSCT. As predicted, OS and RFS in the HSCT group were significantly higher than in the non-HSCT group (Figures 3 and 4, p ⬍ 0.0001 and p ⫽ 0.0002 according to log-rank test).
Prognostic factors Twelve patients (33.3%) received an allogeneic stem cell graft after fGO and salvage chemotherapy. Characteristics are given in Table II. The conditioning regimen was myeloablative in six patients (five patients received busulfan for 4 days with cyclophosphamide for 2 days and one patient received 12 Gy total body irradiation with cyclophosphamide), and non-myeloablative in the six remaining
As shown in Table III, the percentage of blasts in blood, WBC count, performance status and increased SGOT were prognostic factors for OS, but not CD33 expression ratio. The percentage of blasts in blood, performance status, increased SGOT and CD33 expression ratio were prognostic factors for RFS, but not WBC count. Multivariate analysis showed a trend for improved OS and RFS with a good performance status (Table IV).
Figure 2. Probability of relapse-free survival.
Figure 3. Overall survival according to transplant status.
Allogeneic group
GO in relapsed/refractory AML 2329 Table IV. Multivariate analysis.
Prognostic factor Percent blood blasts WBC count Performance status SGOT ⬎ ULN CD33 expression (ratio)
Overall survival, HR, 95% CI, p-value
Relapse-free survival, HR, 95% CI, p-value
1.01 (0.99–1.02), 0.3 1.0 (0.99–1.01), 0.5 1.59 (0.98–2.56), 0.056 1.77 (0.5–5.6), 0.31 –
1.00 (0.99–1.02), 0.34 – 1.44 (0.95–2.18), 0.08 1.92 (0.53–6.9), 0.31 1.01 (0.99–1.02), 0.11
WBC, white blood cell; SGOT, serum glutamic oxaloacetic transaminase; ULN, upper limit of normal; HR, hazard ratio; CI, confidence interval.
Figure 4. Relapse-free survival according to transplant status.
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Discussion This study represents one of the biggest series of fGO with ICT in patients with relapsed or refractory AML (n ⫽ 36). There are very few data on salvage therapy with fGO in patients with very high-risk disease with short CR1 duration (⬍ 6 months) or refractory disease. Publications of studies using fGO in combination with chemotherapy as salvage regimen showed a response rate of 55–80%. However, these studies investigated efficacy in patients with relapsed AML with a CR1 duration of 6 months [20,22], or included a low percentage of 30% and 33% of patients with AML with a CR duration of ⬍ 6 months [3,21]. In the present study, 55% of patients belonged to this high-risk population (22% refractory and 33% CR1 duration ⬍ 6 months) and had a CR rate of 20%. In contrast, patients with CR1 duration ⬎ 6 months had a CR rate of 62.5%, which is very similar to that in the published data. Median RFS and OS after salvage treatment were 2.06 (0.5–44.6) and 2.5 months (0.6–44.6) for the high-risk group, compared to 6.21 (0.4–29.1) and 8.5 months (0.4–34) for the low-risk group with CR1 duration ⬎ 6 months (p ⫽ not significant, log-rank test). In the high-risk population, there is very little chance of achieving CR with standard chemotherapy and consequently of receiving HSCT. However, this study showed an overall response rate (ORR) of 38.8% (CR ⫹ CRp), with 42.8% ORR in relapsed patients and 25.0% ORR in refractory patients. Other salvage regimens without GO reported a CR rate of 11% and 24% in patients with refractory and relapsed AML, respectively [26]. In comparison, another chemotherapy regimen in combination with GO in patients with refractory AML showed a 27% ORR [18]. The addition of fGO to ICT produced promising response rates in a very Table III. Univariate analysis. Prognostic factor Percent blood blasts WBC count Performance status SGOT ⬎ ULN CD33 expression (ratio)
Overall survival, HR, 95% CI, p-value
Relapse-free survival, HR, 95% CI, p-value
1.02 (1.0–1.03), 0.004 1.01 (1.0–1.01), 0.035 1.83 (1.17–2.88), 0.008 3.36 (1.39–8.12), 0.007 NS
1.01 (1.0–1.02), 0.015 NS 1.59 (1.05–2.42), 0.028 3.83 (1.6–9.16), 0.003 1.01 (1.0–1.02), 0.038
WBC, white blood cell; SGOT, serum glutamic oxaloacetic transaminase; ULN, upper limit of normal; HR, hazard ratio; CI, confidence interval; NS, not significant.
high-risk population. However, results must be taken with caution because of the heterogeneity of the chemotherapies used. Although three different ICT regimens were used in combination with GO in the present study, the majority of patients (86.2%) were treated with classic salvage chemotherapy using two or more well-known active drugs in AML. Only 13.8% received cytarabine alone. GO may be combined with different salvage therapies with success. The CD33 expression ratio was also associated with better remission rates and RFS. However, it was not a prognostic factor for OS. The CD33 expression ratio may be a useful tool for more effective screening of patients who may potentially benefit from fGO salvage therapy and achieve a CR, but this must be confirmed in prospective studies. Treatment tolerance is of particular importance in this group of patients previously treated with induction chemotherapy. This study reported induction-related mortality at a rate of 13.8%, which was very similar to treatment-related mortality (18%, 13.8%, 11.1%, 10.4%, 35%, 10%) described with salvage regimens [26–31]. No SOS was reported after allogeneic stem cell transplant in this study. Although the number of patients was relatively small, the use of salvage ICT with fGO does not preclude the subsequent use of allograft. Use of fGO with ICT enabled 12 patients (33%) to receive HSCT, therefore offering a chance of long-term survival. Ten patients were in relapse before salvage treatment and two were refractory. Among the 10 patients in relapse before salvage treatment, according to the Breems classification, one belonged to the low-risk group, four to the intermediate group and five to the high-risk group. Thus, successful salvage treatment and allogeneic stem cell transplant may be offered to all patients, regardless of relapse index group and CR1 duration. The HSCT patient-group showed better survival than patients treated without HSCT. However, the HSCT patient-group included patients with chemosensitive AML, with a clear benefit in terms of survival over non-responders not having received a transplant. To date, there is no standard salvage regimen for patients with refractory or relapsed AML, and many studies have failed to demonstrate the superiority of a given salvage chemotherapy regimen over another. The use of fGO with chemotherapy offers a chance of remission and a possibility of cure with allogeneic stem cell transplant. Despite the limited value due to the small number of patients, this study demonstrated the efficacy and safety of ICT with fGO. HSCT is feasible, without excessive toxicity or SOS.
2330 S. P. Chantepie et al.
Conclusion ICT with fGO induced a 38.8% response rate, offering the possibility of HSCT in 33% of patients. fGO with ICT may be considered in patients with relapsed or very high-risk AML as a bridge to transplant. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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