Acute lymphoma Autologous stem cell transplantation for advanced acute myeloid leukemia

Bone Marrow Transplantation (2002) 29, 297–301  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Acute lympho...
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Bone Marrow Transplantation (2002) 29, 297–301  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt

Acute lymphoma Autologous stem cell transplantation for advanced acute myeloid leukemia CA Linker1, LE Damon1, CA Ries1, WA Navarro1, D Case2 and JL Wolf3 1

University of California, San Francisco, CA, USA; 2Maine Medical Center, Portland, ME, USA; and 3Alta Bates Medical Center, Berkeley, CA, USA

Summary: We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m2 twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (×106/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment. Bone Marrow Transplantation (2002) 29, 297–301. DOI: 10.1038/sj/bmt/1703361 Keywords: autologous transplantation; acute myeloid leukemia

Autologous transplantation is an important treatment modality for patients with acute myeloid leukemia (AML) who are in second or subsequent remission or who have evolved from antecedent myelodysplasia. For such patients, treatment with chemotherapy alone seldom leads to longterm survival. Allogeneic transplantation using a matched Correspondence: Dr C Linker, Room A502, 400 Parnassus Avenue, San Francisco, CA 94143, USA Received 20 September 2001; accepted 25 October 2001

sibling donor is usually considered the treatment of choice for patients with AML in second remission and produces long-term event-free survival (EFS) in 30–40% of patients treated. However, many patients are not candidates for this procedure because of advanced age or lack of a suitable donor and hence are considered candidates for autologous transplantation.1 We have recently reported on a two-step approach to autologous stem cell transplantation for patients with AML in first remission.2 The use of intensive consolidation chemotherapy with high-dose ara-C plus etoposide produced excellent CD34+ stem cell yields and allowed a high percentage of patients to receive the intended transplant. After stem cell transplantation, rapid hematologic recovery resulted in low morbidity and mortality. Since patients with advanced forms of AML are often heavily pre-treated, they are at risk for poor stem cell mobilization as well as increased transplant-associated morbidity and mortality. We report the success of our two-step strategy in mobilizing stem cells, producing rapid engraftment and low morbidity and mortality in this patient group.

Methods Patient selection Patients were enrolled from three centers between December 1993 and December 1998. Twenty-four patients were enrolled from UCSF, three from Maine Medical Center, and one from Alta Bates. All patients gave written informed consent in accord with each Institution’s Committee on Human Research. Eligible patients were over age 16 and up to age 70. Patients were eligible if they had AML in second or third remission, or secondary AML either evolved from myelodysplasia or following chemotherapy given for another malignant disorder. Patients classified as primary induction failure were also eligible if they failed to enter initial remission after induction chemotherapy with 6 days of twice daily high-dose ara-C (HDAC) plus daunorubicin (180 mg/m2) but subsequently achieved remission with salvage chemotherapy. Complete remission was defined as normal bone marrow morphology with ⬍5% blasts, resolution of previously abnormal cytogenetics, no evidence of extramedullary leu-

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kemia, absolute neutrophil count (ANC) ⬎1000/␮l and platelets ⬎100 000/␮l. This remission was required to last at least 30 days prior to study entry. We required adequate organ function with bilirubin ⬍2.0 mg/dl, alkaline phosphatase and aspartate transaminase (AST) ⬍3 times the upper limit of normal and creatinine ⬍2.0 mg/dl. Step 1 – consolidation chemotherapy Patients were treated with ara-C 2000/mg/m2 i.v. over 2 h every 12 h × 8 doses on days 1–4 plus etoposide 40 mg/kg by continuous i.v. infusion over 96 h on days 1–4. All chemotherapy was dosed based on corrected weight defined as ideal weight plus 25% of the difference between actual and ideal weight. G-CSF 5 ␮g/kg subcutaneously daily was started on day 14 of therapy and continued until peripheral blood stem cell collection was completed. The dose of GCSF could be escalated to 10 ␮g/kg if stem cell collection was proceeding slowly. Stem cell collection Stem cell collection was started when the WBC ⬎10 000/␮l. For the first 14 patients, we required a CD34+ cell dose (×106/kg) of 10. In July 1996, the protocol was modified so that the CD34+ target dose was ⬎5. Leukopheresis was performed according to Institutional criteria, processing 12–18 liters of blood daily. A buffy coat was prepared by centrifugation and mixed in M199 media with 5% autologous plasma and 10% DMSO to achieve a final cell concentration of 2.5 × 108 cells/ml. The stem cell product was frozen in a controlled rate freezer and stored in liquid nitrogen. Step 2 – autologous stem cell transplantation Patients were eligible to proceed to transplantation when they had been out of the hospital for at least 4 weeks after completion of consolidation chemotherapy. They had to be in documented complete remission with normal bone marrow morphology, ANC ⬎500/␮l and platelets ⬎50 000/␮l and either improving or stable. We required adequate organ function as defined for study entry plus a cardiac ejection fraction ⬎40% and DLCO ⬎50% predicted. The preparative regimen consisted of busulfan 1 mg/kg orally every 6 h for 16 doses (total dose 16 mg/kg) on days −7 to −4 plus etoposide 60 mg/kg i.v. on day −3. The infusion time for etoposide was 10 h in the first half of patients and subsequently reduced to 4 h. As in step 1, all chemotherapy doses were calculated according to corrected weight. Peripheral blood stem cells were infused on day 0. G-CSF 5 ␮g/kg subcutaneously daily was started on day 0 and continued until ANC ⬎1500/␮l for 2 consecutive days or ⬎5000/␮l for 1 day. Supportive care During consolidation chemotherapy, patients received fluorometholone ophthalmic solution 0.1% two drops four times daily days 1–6. Amphotericin 0.3 mg/kg was started on day 5 of chemotherapy and continued until ANC

Bone Marrow Transplantation

⬍500/␮l. Prophylactic antibiotics against gram-negative bacteria were started when ANC ⬍500/␮l and continued until the resolution of neutropenia (ANC ⬍500/␮l). During autologous stem cell transplantation, amphotericin 0.3 mg/kg was started on day +1 and continued until ANC ⬎500/␮l. Acyclovir was started on day −2 and continued until 1 year after transplantation. Depending on the patient’s ability to take oral medication, the dose was either 200 mg orally three times daily or 2 mg/kg i.v. every 12 h. Prophylactic antibiotics against gram-negative bacteria were started when ANC ⬍500/␮l and continued until the resolution of neutropenia (ANC ⬎500/␮l). Pneumocystis prophylaxis was maintained with trimethoprim/ sulfamethoxazole 160 mg/twice daily twice a week until at least 3 months after transplantation and CD4 lymphocyte count ⬎200/␮l. Statistical evaluation Disease-free survival was calculated by Kaplan–Meier analysis from the date of the start of consolidation chemotherapy. Data were analyzed as of 17 October 2001. Results Patient features A total of 28 patients were enrolled on study and treated (Table 1). The median age was 44. Six patients were over age 60 years and four had a WBC ⬎100 000/␮l. Nine patients were in CR2 and two in CR3. The median duration of first remission was 12 months, and one patient had relapsed after a previous autologous stem cell transplant. Of the CR2/3 patients, two patients had t(15,17), one had inversion 16q, and others were intermediate risk. Six patients had secondary leukemias; four had prior breast cancer treated with chemotherapy (including one autologous stem cell transplant), one had Hodgkin’s disease treated with MOPP, and one had RAEB without prior chemotherapy. Two of the patients with prior breast cancer had t(15,17) and the patient who received prior MOPP had t(8,21) with a clear myelodysplastic prodrome. Eleven patients had ‘primary induction failure’ after receiving HDAC plus daunorubicin. Three of these patients had t(15,17) and subsequently achieved remission with idaTable 1

Patient features

Age (years) WBC (103/␮l) CR 2/3 Secondary AML Primary induction failure Cytogenetics t(15,17) other favorable intermediate poor risk

Median

Range

44 11 Number 11 6 11

(19–69) (1–427)

7 2 18 1

Autologous transplant for AML CA Linker et al

Days, median values (range).

get CD34 cell dose was 2. For the first 14 patients for whom the CD34+ target was 10 × 106/kg, the median number of collections was 2 (1–7). For the subsequent 14 patients in whom the CD34+ target was reduced to 5, the median number of collections was 1 (1–5). Two patients failed to mobilize stem cells. One patient had a streptococcus viridans sepsis with multi-system failure, and was critically ill at the time of attempted collection. A CD34+ cell dose of 3.7 × 106/kg was obtained and this patient did not proceed to transplant. A second patient who failed to mobilize any CD34+ cells had pneumonia with influenza A prior to attempted collection. Overall, 93% of patients achieved the CD34+ target.

Table 3

Step 2 – autologous stem cell transplantation

Table 2

Hematologic recovery Step 1

ANC (/␮l) ⬎500 ⬎1000 Platelets (/␮l) ⬎20 000 ⬎50 000 ⬎100 000 No. platelet Tx No. units RBC

Step 2

21 (17–31) 22 (17–33)

+9 (8–13) +10 (8–14)

28 32 36 7 8

+13 +21 +30 3 4

(11–118) (18–223) (18–351) (1–57) (1–44)

(8–37) (8–191) (11–508) (1–13) (0–11)

Non-hematologic toxicity

rubicin plus all-trans retinoic acid (ATRA). The other eight patients achieved remission after salvage therapy using the combination of idarubicin, HDAC, and high-dose etoposide. One patient had monosomy 7. The median interval from achieving remission to study entry was 39 days (30–234), and two patients had an interval greater than 90 days. No patient received post-remission therapy after achieving his or her current remission and before study entry.

Twenty-six patients (93% of the group) proceeded to transplantation. Engraftment after stem cell infusion was rapid with an ANC ⬎500 by day +9, and no patients reaching an ANC ⬎1000 at later than day +14 (Table 2). The total duration of neutropenia (ANC ⬍500) was 6 (4–11) days. Similarly, platelet engraftment was rapid with platelets greater than 20 000/␮l by day +13, and only four patients took longer than 30 days to reach this level. Patients left the hospital on median day +17 and all patients were discharged within 4 weeks (Table 3). Non-hematologic toxicity was very acceptable. Patients required a median of 7 days of parenteral nutrition and 7 days of narcotic analgesia. Only four patients required more than 2 weeks of parenteral nutrition. Hepatotoxicity was modest with only one patient having a peak bilirubin ⬎3 mg/dl. There was one treatment-related death in a 63-year-old woman in third remission who died of multi-system failure.

Step 1 – consolidation chemotherapy

Treatment outcome

Consolidation chemotherapy was generally well tolerated. Hematologic toxicity was as expected with a median of 15 (9–22) days with an ANC ⬍500/␮l (Table 2). There was little non-hematologic toxicity with most patients not requiring parenteral nutrition (TPN) or intravenous narcotics (Table 3). Only four patients required more than 2 weeks of TPN. There was little hepatotoxicity and only two patients had bilirubin ⬎3 mg/dl. There were no cases of neurotoxicity. There were no treatment-related deaths during consolidation, but one patient experienced life-threatening multi-system failure after streptococcus viridans sepsis.

Twenty-eight patients were enrolled on the study. Both patients who failed to proceed to transplantation because of failure to mobilize stem cells remain in continuous remission, one with no additional therapy (5.6 years) and one after allogeneic transplantation (2.9 years) (Table 5). Of 26 patients transplanted, there was one treatment-related death. Twelve patients relapsed a median of 6 months after transplantation (9 months after study entry). Of the 12 relapses, all but two occurred within the first year after

Step 1 Days TPN Days narcotics Hospital discharge Peak bilirubin (mg/dl)

0 0 28 1.3

(0–33) (0–7) (19–88) (0.7–43)

Step 2 7 7 +17 1.1

(0–24) (0–17) (12–28) (0.4–3.2)

Days, median values (range).

Table 5

Outcome

Stem cell collection

All

M3

Stem cell collection began on a median of day 26 (Table 4). Overall, the median number of collections to reach the tarTable 4

Stem cell collection

Start day No. collections CD34+ (×106/kg) CFU-GM (×104/kg) No. collections to CD34+ ⬎5 (106/kg) Median values (range).

26 (19–44) 2 (1–7) 13.6 (0–236) 168 (23–1736) 1 (1–7)

299

Non-M3 CR2/3 Secondary PIF

Step 1 Fail to mobilize

28 2

7 0

9 0

4 0

8 2

Step 2 death relapse Continuing remission

26 1 12 13a

7 0 0 7

9 1 6 2

4 0 3 1

6 0 3 3a

a In addition, two patients who failed to mobilize stem cells and hence were not transplanted on study remain in continued remission.

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1.0

Discussion

Event-free survival

0.8

0.6 EFS 54% 0.4

0.2

0 0

2

4 Years

6

8

Figure 1 EFS of all patients. Error bars indicate 95% confidence intervals.

transplantation, and all occurred less than 2 years after transplantation. With median follow-up of 5.4 years (2.8–7.9) EFS of all patients entered on the study is 54 ± 18% (Figure 1). The most powerful prognostic factor was cytogenetic changes (Figure 2). All seven patients with t(15,17) remained in remission. Two of these patients were in second remission, three had failed primary induction therapy, and two had developed leukemia after prior chemotherapy, including one autologous transplant for breast cancer. Median followup for these patients is 5.4 years (2.8–6.3). For the 21 patients without t(15,17) with median follow-up of 3.7 years (2.9–7.9) EFS is 38 ± 20%.

1.0

M3 EFS 100%

Event-free survival

0.8

0.6

0.4 EFS 38% 0.2

0 0

2

4 Years

6

8

Figure 2 EFS of patients according to cytogenetic risk, t(15,17) vs others. Error bars indicate 95% confidence intervals. Bone Marrow Transplantation

This two-step approach to autologous stem cell transplantation appears to make this procedure feasible and accessible to the large majority of patients with AML beyond first remission. Twenty-six of 28 (93%) patients received the full intended treatment. This chemotherapy regimen with high-dose ara-C plus etoposide appears extremely effective in mobilizing stem cells, and CD34+ cell yield was very similar to that seen in patients with first remission AML.2 Inability to mobilize is infrequent and in this study, appeared related to uncontrolled infection. The CD34+ cell target ⬎5 × 106/kg was collected in a median of one apheresis, and a target cell dose ⬎10 × 106/kg was collected in two aphereses. With the high stem cell doses infused, engraftment was rapid and neutropenia was brief. This likely contributed to the relative safety of the procedure with one treatment-related death (TRM 4%) in a group of patients with extensive prior treatment. As in our experience with first remission patients, the rapid engraftment appears to have a beneficial affect on non-hematologic toxicity. Hepatotoxicity was minimal and we did not see severe prolonged mucosal and skin toxicity as we had with the same preparative regimen given with purged autologous bone marrow transplant.3 The treatment outcome data are encouraging and with minimum follow-up beyond the time of the latest relapse observed, the data are mature and unlikely to change significantly. Some of the favorable outcome is related to patient selection with excellent outcomes in the patients with t(15,17). Others have reported similarly favorable outcomes with autologous stem cell transplant in this patient group.4,5 The patients in second remission had a median duration of first remission of 12 months. Long first remission duration has been associated with improved outcomes and the four patients in this report in second or subsequent remission who had long-term EFS had initial remission durations of 11–15 months.6 Our data are consistent with other reports showing the ability of autologous transplantation to generate long-term DFS in patients with advanced AML.1,2,6–9 Autologous transplantation for patients in second remission has produced EFS in approximately 30% of patients. This is an outcome not very different from that seen with allogeneic transplantation. Preliminary data also suggest that this approach can be effective in at least 20% of patients with advanced myelodysplastic syndromes.10 Peripheral blood stem cell transplantation has some significant advantages compared to bone marrow transplantation for patients with AML. Engraftment is significantly faster, and this undoubtedly explains the lower treatmentrelated mortality.11–14 Although there was initial concern that the relapse rate may be higher using unpurged peripheral blood stem cells, a retrospective comparison suggests that relapse rates with stem cells are equivalent to those seen with bone marrow.15 In summary, the treatment approach outlined in this report allows for excellent stem cell recovery, rapid engraftment, and the ability to carry out autologous transplantation with acceptable morbidity and low mortality in a group of patients with advanced forms of AML. This type

Autologous transplant for AML CA Linker et al

of treatment appears to be the best available therapy for such patients who lack a matched sibling donor or who are not optimal candidates for allogeneic transplantation because of age or co-morbidities.

References 1 Gorin NC. Autologous stem cell transplantation in acute myelocytic leukemia. Blood 1998; 92: 1073–1090. 2 Linker CA, Ries CA, Damon LE, Sayre P. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant 2000; 6: 50–57. 3 Linker CA, Ries CA, Damon LE, Rugo HS. Autologous bone marrow transplantation for acute myeloid leukemia using 4hydroperoxy cyclophosphamide purged bone marrow and the bulsulfan etoposide preparative regimen: a follow-up report. Bone Marrow Transplant 1998; 22: 865–872. 4 Meloni G, Diverio D, Vignetti M, Avvisati G. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pre-transplant minimal residual disease assessment by reverse transcription polymerase chain reaction of the PMLRAR alpha fusion gene. Blood 1997; 90: 131–1325. 5 Sanz MA, Arcese W, DelaRubia J, LoCoco F. Stem cell transplantation for acute promyelocytic leukemia in the ATRA era: a survey of the European blood and marrow transplantation group. Blood 2000; 96: 522a (Abstr. 2247). 6 Meloni G, Vignetti M, Avvisati G et al. BAVC regimen: an autograft for acute myelogeneous leukemia in second complete remission. Bone Marrow Transplant 1996; 18: 693–698. 7 Gorin NC, Labopin M, Fouillard L et al. Retrospective evaluation of autologous bone marrow transplantation vs allogeneic bone marrow transplantation from an HLA-identical, related

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donor in acute myelocytic leukemia: a study of the European Cooperative Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1996; 18: 111–117. Stein AS, O’Donnell MR, Chai A et al. In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogeneous leukemia in first complete remission. J Clin Oncol 1996; 14: 2206–2216. Califaretti N, Davidson M, Abraham R et al. Autologous bone marrow transplant for acute myelogeneous leukemia in second or subsequent remission. Blood 1998; 92 (Suppl. 1): 294a (Abstr. 1203). DeWitte T, Van Biezen, Hermans J et al. Autologous bone marrow transplantation for patients with myelodysplastic syndrome or acute myeloid leukemia following MDS. Blood 1997; 90: 3853–357. Vellenga E, vanPutten WLJ, Boogarets MA et al. Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia? Bone Marrow Transplant 1999; 23: 1279–1282. Visiani G, Lemoli RM, Tosi P et al. Use of peripheral blood stem cells for autologous transplantation in acute myeloid leukemia patients allows faster engraftment and equivalent disease-free survival compared with bone marrow cells. Bone Marrow Transplant 1999; 24: 467–472. Martin C, Torres A, Leon A et al. Autologous peripheral blood stem cell transplantation mobilized with GCSF in AML in first complete remission: role of intensification therapy in outcome. Bone Marrow Transplant 1998; 21: 375–382. Gondo H, Harada M, Miyamoto T et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant 1997; 20: 821–826. Reiffers J, Lapin M, Sanz M, Kobling M. Autologous blood vs marrow transplantation for acute myeloid leukemia in complete remission: an EBMT retrospective analysis. Bone Marrow Transplant 2000; 25: 1115–1119.

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