Med Oncol (2013) 30:744 DOI 10.1007/s12032-013-0744-z
ORIGINAL PAPER
An effective reinduction regimen for first relapse of adult acute lymphoblastic leukemia Ibrahim Aldoss • Vinod Pullarkat • Ravindra Patel Kristy Watkins • Ann Mohrbacher • Alexandra M. Levine • Dan Douer
•
Received: 4 June 2013 / Accepted: 2 October 2013 / Published online: 18 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed/ refractory acute lymphoblastic leukemia (ALL), and this represents a major barrier for performing allogeneic hematopoietic stem cell transplant (HSCT), the only potentially curative treatment. We conducted in adults with first relapse of ALL, a prospective clinical trial with intensive regimen derived from the pediatric BerlinFrankfurt-Muenster-85 protocol, with addition of a continuous infusional multi-agent chemotherapy in phase II induction followed by consolidation with alternating monthly cycles. Objectives of this study included CR rate, leukemia-free survival (LFS) and toxicity of the regimen in adults. We report the outcome of 19 patients (19–51 years of age) treated prospectively on the study, as well as a subsequent cohort of 31 patients (18–53 years of age) treated off the study. Thirteen of 19 (68 %) patients from the initial prospective study achieved CR, and the median overall survival (OS) of these 13 CR patients was 10.3 months. The median OS and LFS of all 19 patients were 5.6 and 4.3 months, respectively. The regimen was well tolerated, and no grade 4 non-hematological toxicity I. Aldoss (&) V. Pullarkat R. Patel K. Watkins A. Mohrbacher Jane Anne Nohl Division of Hematology and Center for Study of Blood Diseases, University of Southern California (USC), Room 3461, 1441 Eastlake Avenus, Los Angeles, CA 90089, USA e-mail: [email protected] A. M. Levine City of Hope National Medical Center, Duarte, CA, USA D. Douer Leukemia Service, Department of Medicine, Memorial SloanKettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
was observed. Of the 31 patients treated off the study and analyzed retrospectively, 16 (52 %) achieved CR. After including all 50 patients, the CR rate was 58 %. The regimen used in this trial appears to be feasible and effective salvage therapy option for adult patients younger than age 55 with relapsed ALL, produced a high CR rate and could facilitate subsequent allogeneic HSCT. Keywords Acute lymphoblastic leukemia Adult Relapse Reinduction
Introduction While the cure rate of pediatric acute lymphoblastic leukemia (ALL) is approaching 90 % [1], the outcome of adult ALL drastically lags behind, primarily due to disease relapse, with less than half of the adults being cured and becoming long-term survivors [2, 3]. Adopting pediatricderived regimens in adult ALL have been proven to be feasible and effective [4, 5]. The prognosis of adult ALL patients who relapse or are refractory to induction therapy is dismal, and long-term survival is only around 10 % [6–9]. The primary purpose of salvage therapy in relapsed/refractory ALL is to achieve complete remission (CR) in order to subsequently perform allogeneic hematopoietic stem cell transplantation (HSCT) as soon as possible, given the fact that remissions beyond the first CR are universally not durable. Allogeneic HSCT is currently the only curative modality for refractory/ relapsed adult ALL, and the outcome of HSCT is superior when it is performed during remission rather than in patients with active leukemia [6]. Therefore, the challenge is to achieve a relatively durable second CR (CR2) with salvage therapy as a bridge to HSCT. With current salvage
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regimens, only around a third of relapsed/refractory adult ALL patients achieve CR2 or higher [6, 8, 10]. In an attempt to improve the CR rates of relapsed adult ALL patients and allow more patients to become candidates for HSCT, we designed a regimen modeled after the Berlin-Frankfurt-Muenster (BFM)-85 German Cooperative Group trial which proved to be highly effective in relapsed pediatric ALL [11]. The BFM-85 pediatric trial included induction with high-dose methotrexate and cytosine arabinoside, followed by post-remission therapy consisting of 2 alternating multi-agent treatment blocks and achieved in heavily pretreated children, a CR rate of 90 % with an event-free survival at 5 years of 30 %. We modified this pediatric protocol by adding a second induction cycle of continuous infusion of vincristine, adriamycin and dexamethasone (VAD) with ifosfamide in all patients regardless of whether they achieved a CR after the first cycle of induction therapy [12, 13]. Herein, we report the results of our prospective trial in adults with relapsed ALL as well as the outcome of a retrospective cohort treated subsequently.
Med Oncol (2013) 30:744 Table 1 Chemotherapy protocol (induction phase I and II) Induction phase I Allopurinol
300 mg/day PO days 1–15
Prednisone
100 mg/m2 PO days 1–8 and 15–21
Vincristine
1.5 mg/m2 (max 2 mg) intravenously (IV) on days 1, 8, 15 and 22
Cytarabine
3 g/m2 IV over 3 h bid for 4 doses on days 1 and 2
Methotrexate
1 g/m2 continuous IV infusion (CIV) over 36 h on day 15
Leucovorin
30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6 doses
L-Asparaginase
10,000 units/m2/dose IV on days 3, 4, 16 and 17
Filgrastim
5 mcg/kg/day SC injections were started 24 h after the end of cytosine arabinoside
Induction phase 2 Dexamethasone Ifosfamide
500 mg/m2/day IV on days 1–4
Mesna
500 mg/m2/day IV immediately before ifosfamide on days 1–4
Vincristine
0.4 mg/m2 (max 2 mg) CIV on days 1–4
Adriamycin
12 mg/m2 CIV on days 1–4
Filgrastim
Patients and methods Patients The phase II prospective study as well as the analysis of the retrospective data were approved by the Institutional Review Board of Keck School of Medicine of the University of Southern California. The eligibility criteria for the prospective study included patients with ALL who relapsed or were refractory to chemotherapy, age range of 17–55 years, Karnofsky performance status of [50 % and adequate hepatic and renal function. The diagnosis of relapsed ALL was based on bone marrow morphology and immunophenotypic analysis. Cytogenetic characterization was not required for study entry. Because of the intensity of our study regimen, we limited our study to adults younger than 55 years of age. Patients with central nervous system (CNS) involvement were eligible for this protocol if bone marrow was involved as well. Exclusion criteria were congestive heart failure or ejection fraction \45 %, other severe medical or psychiatric conditions, positive HIV test or known hypersensitivity to E coli-derived proteins. No patient had received high-dose cytosine arabinoside or high-dose methotrexate at any time prior to enrollment in this trial. Therapy The induction protocol is summarized in Table 1 and was mostly adapted from the BFM-85. It is consisted of two
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Starting on days 28–30 40 mg/day PO on days 1–4, 9 to 12
Intrathecal Therapy Methotrexate
5 mcg/kg/day SC injections were started on day 5 Prophylaxis starting on day 1 or 2 of phase II 12 mg on day 1 or 2
Cytosine arabinoside
30 mg on day 1 or 2
Hydrocortisone
15 mg on day 1 or 2
induction phases. The first phase included high-dose cytosine arabinoside followed 2 weeks later by high-dose methotrexate; E. Coli asparaginase was given for 2 days after each agent. The second induction phase was given irrespective of whether or not the patients achieved a CR and included VAD as reported by Kantarjian et al. [11–13] and intensified with addition of ifosfamide. Prophylactic filgrastim 5 mcg/kg/day was given 24 h after administration of each of the induction phases. Consolidation therapy consisted of alternating blocks of multi-agent chemotherapy for total of 8 cycles (4 cycles each block) (Table 2). Filgrastim 5 mcg/kg was administered daily in the consolidation blocks when the ANC was \0.5 9 109/L. Intrathecal (IT) prophylaxis was administered on days 1 or 2 of induction phase II and on day 8 of each consolidation block. If the CNS was involved prior to induction, IT therapy was administered twice weekly until CSF sterilization, then weekly for 1 month, followed by cranial radiotherapy with 18 cGy (if not given during first remission). After the eighth consolidation block, patients continued with maintenance chemotherapy (Table 2). In all treatment phases, except for the maintenance phase,
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Table 2 Chemotherapy protocol (consolidation and maintenance)
Table 3 Patient Characteristics
Consolidation block I Prednisone
100 mg/m2 PO days 1–5
6-Mercaptopurine
100 mg/m2/day PO on days 1–5 2
Vincristine
1.5 mg/m (max 2 mg) intravenously (IV) on day 1
Cytosine arabinoside
300 mg/m2 IV on day 1
VP-16
Prospective cohort
Retrospective cohort
Number of patients
19
31
Period of cohort enrollment
1993–1999
2004–2013
Median age, years (range)
25 (19–51)
36 (18–53)
Cell type, No
2
Precursor B cell
16
29
2
T cell
3
2
Median WBC at relapse (range), 109/L
13 (2–70.3)
5 (1.5–116)
Median previous CR duration, months (range)
10.5 (3–60)
16 (1–79)
1 (1)
1 (1–2)
19/0
28/3
100 mg/m /day PO on days 1 to 5
Methotrexate
500 mg/m IV infusion over 4 h on day 8
Leucovorin
30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6 doses
Filgrastim
5 mcg/kg/day SC injections if ANC \ 0.5 x 109/L until an ANC of C 10 x 109/L
Consolidation block II 6-Thioguanine
100 mg/m2/day PO on days 1–5
Dexamethasone
20 mg/m2/day PO on days 1–5
Ifosfamide
1.33 g/m2 IV on day 1
Median prior lines of therapy, No (range)
Mesna
1.33 g mg/m2 IV immediately before ifosfamide
Disease status
Vincristine
2
1.5 mg/m (max 2 mg) CIV on day 1 2
Methotrexate
500 mg/m IV infusion over 4 h on day 8
Leucovorin
30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6 doses 5 mcg/kg/day SC injections if ANC \ 0.5 9 109/ L until ANC of C 10 x 109/L
Filgrastim
The consolidation block I and block II are rotated for a total of 8 cycles (each block 4 times). Each block is given at intervals of 28 days provided ANC [1,000 and platelets are [75,0000 Intrathecal therapy
Prophylaxis starting on day 8 of block I and block II. If CNS involvement, then 2 times weekly until CSF sterilization. Then, IT therapy continued on a weekly basis for 1 month.
Maintenance therapy Methotrexate
50 mg/m2 PO once weekly for 2 years
6-Thioguanine
50 mg/m2 PO on daily basis for 2 years.
chemotherapy doses were not modified for hematological toxicity. Statistical considerations This was a pilot, phase II, single-institution, prospective clinical trial. The primary objective of the study was the CR rate after the two phases of induction therapy. Secondary objectives were LFS, regimen toxicity and number of days for until neutrophil count recovery after each cycle of induction. CR was determined by morphologic evaluation of the bone marrow on day 28 of induction and defined as cellularity greater than 20 %, maturation of all cell lines, less than 5 % marrow blasts, peripheral ANC [1.5 9 109/L and a platelet count of [100 9 109/L.
Relapsed/ refractory
Disease location at relapse BM only
19
23
BM ? CNS
5
Non-CNS extramedullary (± BM)
4
Cytogenetics [No]
Unavailable
Ph-positive [3], NK [18], del(9) [1], del(1) [1], der(11) [1], t(1;2) [1], unknown [6]
Previous chemotherapy
Unavailable
Modified BFM regimen = 25 Unknown = 6
BM bone marrow, CNS central nervous system
Relapse from CR was defined as the occurrence of any of the following: (1) greater than 5 % blasts in the bone marrow, not attributable to the regeneration of bone marrow following chemotherapy-induced aplasia, (2) reappearance of leukemic blasts in the peripheral blood or (3) biopsy-proven extramedullary leukemia. Treatment failure was defined as either resistant disease or persistence of bone marrow aplasia. Resistant disease was defined as the lack of CR in surviving patients despite receipt of both phases of induction therapy. All patients were considered eligible for response and toxicity assessment. Leukemia-free survival (LFS) was calculated from the time of CR to the time of relapse, last follow-up or death. Overall survival (OS) was calculated from the beginning of treatment to the time of death. The survival and remission duration curves were calculated using standard Kaplan–Meier methodology.
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Table 4 Outcomes
CR, N (%)
Prospective cohort
Retrospective cohort
13 (68 %)
16 (52 %)
Transplanted patients, N (%)
1 (5 %)
9 (29 %)
Refractory disease, N (%)
1 (5 %)
12 (39 %)
Death during induction, N (%)
5 (26 %)
3 (10 %)
OS (months)
5.6
16.1
Results Patient characteristics Fourteen men and 5 women were enrolled in our study between August 1993 and June 1999. Patient characteristics are shown in Table 3. The study was stopped due to slow patient accrual before the planned sample size of 25 patients was reached. Precursor B cell ALL was diagnosed in 16 patients, while three patients had T cell ALL. All patients had first relapse of ALL after a median of 10.5 (range, 3–60) months from initial diagnosis. The median age of patients was 25 years (range, 19–51). The median white blood cell count (WBC) at the time of relapse was 13 9 109/L (range, 2–70.3). Response to therapy The results of the induction therapy are summarized in Table 4. Thirteen of the 19 patients (68 %) achieved a CR (95 CI, 43–87 %). Of those 13, 11 (85 %) did so after receiving the initial phase of the induction therapy. The median time to CR from the start of the induction therapy was 28 days (range, 20–94). Of the 6 (31 %) patients who failed to achieve CR, 1 had primary refractory disease, while the others died of treatment-related infections or hemorrhage (including 2 died during first induction and 3 during second induction). Except for one, no patient underwent allogeneic HSCT. Reasons for inability to proceed to HSCT included early relapse, lack of suitable donor or socioeconomic reasons. All 13 patients who achieved CR proceeded to the postremission phase of the protocol. Only 7 patients completed between 1 and 3 consolidation blocks; no patients from the prospective cohort completed all of the consolidation blocks. The median OS of all 19 patients was 5.6 months (Fig. 1). However, the 13 patients who achieved CR had a median OS of 10.3 months. Eighteen of the 19 (95 %) study patients died during the course of the trial. The causes of death of the 18 patients were as follows: 11 from disease progression, 5 of infection, 1 of bleeding and 1 of unrelated causes. One patient underwent successful
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allogeneic BMT and become a long-term survivor. The median LFS was 4.3 months (Fig. 2). Hematologic recovery after chemotherapy and myelosuppression-associated complications All patients experienced severe bone marrow suppression with marked thrombocytopenia and neutropenia. Febrile episodes occurred in 18 patients. After induction therapy, 4 (21 %) patients died of documented infections and 1 patient died from bleeding during bone marrow aplasia (grade 5 toxicity). The median duration of recovery to ANC of greater than 0.5 9 109/L during the first induction phase was 21 days (range, 14–78) and to platelet count greater than 20 9 109/L was 28 days (range, 11–89). Non-hematologic toxicity No instances of grade 4 non-hematologic toxicity were observed (Fig. 3). The most common toxicity was grade 1 or 2 nausea/vomiting in 10 (53 %) of patients. Grade 3 liver toxicity was observed in 2 patients (11 %), while grade 1 or 2 liver toxicity was seen in 9 patients (47 %). Diarrhea of grade 1 or 2 occurred in 5 (26 %) of patients and grade 3 in only 1 (5 %) patient. Stomatitis occurred in 6 (31 %) patients and was grade 1 or 2 in 26 % of patients and grade 3 in 5 % of patients. Grade 1 or 2 skin rash was seen in 3 (16 %) patients. Outcomes of patients treated off the study Due to the slow accrual and lack of continuous funding, the study was closed prematurely after enrolling 19 patients. However, given the promising high rate of remission observed in the prospective trial and the absence of a standard approach, this regimen became our preferred salvage therapy for refractory/relapsed ALL. Subsequently, we retrospectively reviewed the outcome of a cohort of 43 consecutive patients treated with same regimen off study between 2004 and 2013, and a time period was chosen due to the availability of electronic medical records which made data review feasible. This analysis was limited to adult patients younger than 55 years with relapsed/refractory ALL who were treated with same regimen. However, we excluded from the analysis, cases with isolated CNS relapse as well as cases with insufficient data. Patients who did not achieve CR with the first cycle of salvage induction therapy were deemed refractory and allocated to different treatment in contrast to the prospective study where cycle two of induction therapy was administered prior to classifying the patient as refractory. Toxicity data were not collected due to the retrospective nature of the analysis.
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Fig. 1 OS. Prospective (left) and retrospective (right)
Fig. 2 LFS
pediatric-inspired intensive regimen (81 %) [14]. Of the 31 patients treated with this regimen, 16 (52 %) achieved CR, 3 (10 %) died during induction therapy with bone marrow aplasia and 12 (39 %) were refractory to induction therapy. Only 2 patients successfully completed all cycles of consolidation therapy and continued on the maintenance phase of the regimen. In all other patients in CR, the regimen was discontinued due to relapse or proceeding to HSCT. Nine patients subsequently underwent allogeneic HSCT. The median OS for patients included in the retrospective analysis was 16.1 months (Fig. 1). The pooled analysis for 50 patients (study = 19 and off study = 31), 29 (58 %) patients treated with this regimen achieved a CR and induction-related mortality of 16 %. The total number of patients who underwent allogeneic HSCT was 10.
Discussion
Fig. 3 Toxicities
Among the 43 patients who screened for retrospective analysis, 12 were excluded, and the reason of exclusion was as follows: 6 had only isolated CNS relapse, 4 were older than 55 years of age and 2 had insufficient data to confirm receiving the regimen. Therefore, only 31 patients were suitable for analysis, and the median age was 36 years. Patient characteristics are shown in Table 3. All of these patients were refractory or had relapsed following intensive first-line therapy, and the majority (97 %) of patients had received only one prior line of therapy, most commonly a
No standard salvage therapy exists for relapsed/refractory adult ALL. Various salvage regimens achieve CR in only a third of the patients with relapsed/refractory ALL, and leukemia resistance remains the leading cause of death in these patients, and it dwarfs the treatment-related mortality from any regimen [6, 8, 10]. The low CR rate for the current salvage regimens in adult ALL presents the main barrier for bridging patients to allogeneic HSCT. Achieving a durable CR is a key step for a successful HSCT, and it is one of the major limiting factors to performing HSCT besides donor availability and socioeconomic obstacles. In this study, we investigated the concept of intensive chemotherapy with high-dose methotrexate and cytosine arabinoside integrated with a continuous infusional regimen followed by alternating blocks of consolidation therapy. This concept was successfully applied in earlier pediatric studies and provided the impetus for our trial [11– 13]. Our aim in the study was to achieve a sufficiently durable second remission in relapsed adult ALL in order to render more patients candidates for HSCT and thereby be potentially cured.
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The main finding in this study was the remarkable high CR rate of 68 % in the prospective cohort which compares favorably with any salvage regimen for refractory/relapsed ALL. However, the CR rate was slightly lower in the retrospective cohort probably due to less stringent eligibility criteria as well as not mandating the second cycle of induction in patients who did not achieve CR with the first cycle in contrast to patients treated prospectively. In contrast to the prospectively treated patients, patients in the retrospective cohort were treated during a later time period and often had the exposure to more intensive prior therapy mainly an augmented pediatric-like regimen with highdose methotrexate and peg-asparaginase [14]. Of the 29 patients who achieved CR, only 10 (34 %) underwent allogeneic HSCT. The observed low transplant rate can be attributed to various socioeconomic barriers, availability of donor and disease relapsed before the transplant is ready. But the major obstacle was a timely availability of suitable donors for allogeneic HSCT during the time period during which this study was conducted. Nowadays, this would be a lesser a factor with the availability of a larger pool of matched unrelated donors and other alternate donor sources such as umbilical cord blood and haploidentical donors. Increased use of alternate donor sources particularly haploidentical donors should allow a majority of patients who achieve CR with this regimen to proceed to allogeneic HSCT. Therefore, despite short remission duration, the high CR rate achieved should allow more patients to receive an allogeneic HSCT. Transplant outcomes in the study could not be evaluated as our institution did not have an allogeneic program, and eligible patients were referred to other institutions for HSCT. In spite of the high CR rate seen in the study, the median LFS and OS of the prospective cohort were only 4.3 and 5.6 months, respectively, and these durations are in concordance with previous reports [7, 8, 10]. This is related to the low number of patients who underwent HSCT in CR2, as only one patient underwent HSCT in the prospective cohort and became a long-term survivor. In a retrospective analysis of 547 adults with relapsed ALL from the German Multicenter Study Group for Adult ALL (GMALL), none of the patients who had not undergone HSCT in CR2 became a long-term survivor, which highlights the crucial role of early HSCT in curing relapsed adult ALL [6]. Therefore, any salvage chemotherapy regimen can only be considered a bridge to allogeneic HSCT at the present time. Interestingly, the median OS was longer in the retrospective cohort, which might be related to more patients undergoing HSCT, variation in patients baseline characteristics (longer previous CR duration) and improved supportive care in the more recent years of treatment (2000s vs. 1990s).
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Our unusually high CR rate of 68 % and especially the low rate of disease resistance could be related to various factors including (1) an intense induction therapy regimen that included high-dose cytosine arabinoside and methotrexate in patients who had mostly not received prior high doses of these agents. (2) The sequencing of L-asparaginase when given immediately following high doses of methotrexate or cytosine arabinoside (with so called ‘‘Capizzi effect’’), which has previously shown to induce CR rates of half of the patients with relapsed disease [11, 15]; and (3) the relatively young age of the patients in our study. Our regimen may be of special benefit to the relapsed adult ALL patients who have not already received multiple doses high doses of cytosine arabinoside plus methotrexate, for example in those who had received the commonly used hyper-CVAD front line regimen. Sixteen percent of all patients died during induction therapy, which is in the range of other reports [10, 16]. Although hematological toxicities were common, nonhematological toxicities were manageable with no grade 4 toxicity and infrequent grade 3 toxicities observed in the prospective cohort. The consolidation phase of this regimen is also safe with acceptable non-hematologic toxicity, and it is mainly administered in the outpatient setting. However, it was not able to maintain a durable remission, which is in line with the known short second CR in adult ALL patients who are treated with chemotherapy alone. Salvage therapy for relapsed refractory ALL is evolving with development of active novel targeted agents [17]. Our regimen could serve as a back bone chemotherapy regimen for incorporation of these novel agents in order to further improve CR rates thereby improving the dismal long-term outcome of adult patients with relapsed/refractory ALL. Acknowledgments This work was partially supported in part by a grant from Amgen Inc. Conflict of interest
All authors disclose no conflict of interest.
References 1. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–74. 2. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ ECOG E2993. Blood. 2005;106:3760–7. 3. Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA94 trial. J Clin Oncol. 2004;22:4075–86. 4. Goekbuget N, Baumann A, Beck J, et al. PEG-Asparaginase Intensification In Adult Acute Lymphoblastic Leukemia (ALL):
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Significant Improvement of Outcome with Moderate Increase of Liver Toxicity In the German Multicenter Study Group for Adult ALL (GMALL) Study 07/2003. ASH Annual Meeting Abstracts 2010;116: 494. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009;27(6):911–8. Go¨kbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performed of stem cell transplantation. Blood. 2012;120:2032–41. Fielding AK, Richards SM, Chopra R, Lazarus HM, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50. Oriol A, Vives S, Herna´ndez-Rivas JM, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica. 2010;95:589–96. Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21:1907–14. Kantarjian HM, Thomas D, Ravandi F, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer. 2010;116:5568–74.
Page 7 of 7 11. Henze G, Fengler R, Hartmann R, et al. Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM Group. Blood. 1991;78:1166–72. 12. Kantarjian HM, Walters RS, Keating MJ, Barlogie B, McCredie KB, Freireich EJ. Experience with vincristine, doxorubicin and dexamethasone, VAD chemotherapy in adults with refractory acute lymphocytic leukemia. Cancer. 1989;64:16–22. 13. Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18:547–61. 14. Douer D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based modification of intravenous pegylated asparaginase dosing in the context of a ‘‘pediatric-inspired’’ protocol in adults with newly diagnosed acute lymphoblastic leukemia (ALL). Blood (ASH Annual Meeting Abstracts). 2012;120:1495. 15. Capizzi RL. Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells. Cancer Treat Rep. 1981;65:115–21. 16. Faderl S, Thomas DA, O’Brien S, et al. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011;11:54–9. 17. Douer D. What is the impact, present and future, of novel targeted agents in acute lymphoblastic leukemia? Best Pract Res Clin Hematol. 2012;25:453–64.
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ORIGINAL PAPER
An effective reinduction regimen for first relapse of adult acute lymphoblastic leukemia Ibrahim Aldoss • Vinod Pullarkat • Ravindra Patel Kristy Watkins • Ann Mohrbacher • Alexandra M. Levine • Dan Douer
•
Received: 4 June 2013 / Accepted: 2 October 2013 / Published online: 18 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed/ refractory acute lymphoblastic leukemia (ALL), and this represents a major barrier for performing allogeneic hematopoietic stem cell transplant (HSCT), the only potentially curative treatment. We conducted in adults with first relapse of ALL, a prospective clinical trial with intensive regimen derived from the pediatric BerlinFrankfurt-Muenster-85 protocol, with addition of a continuous infusional multi-agent chemotherapy in phase II induction followed by consolidation with alternating monthly cycles. Objectives of this study included CR rate, leukemia-free survival (LFS) and toxicity of the regimen in adults. We report the outcome of 19 patients (19–51 years of age) treated prospectively on the study, as well as a subsequent cohort of 31 patients (18–53 years of age) treated off the study. Thirteen of 19 (68 %) patients from the initial prospective study achieved CR, and the median overall survival (OS) of these 13 CR patients was 10.3 months. The median OS and LFS of all 19 patients were 5.6 and 4.3 months, respectively. The regimen was well tolerated, and no grade 4 non-hematological toxicity I. Aldoss (&) V. Pullarkat R. Patel K. Watkins A. Mohrbacher Jane Anne Nohl Division of Hematology and Center for Study of Blood Diseases, University of Southern California (USC), Room 3461, 1441 Eastlake Avenus, Los Angeles, CA 90089, USA e-mail: [email protected] A. M. Levine City of Hope National Medical Center, Duarte, CA, USA D. Douer Leukemia Service, Department of Medicine, Memorial SloanKettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
was observed. Of the 31 patients treated off the study and analyzed retrospectively, 16 (52 %) achieved CR. After including all 50 patients, the CR rate was 58 %. The regimen used in this trial appears to be feasible and effective salvage therapy option for adult patients younger than age 55 with relapsed ALL, produced a high CR rate and could facilitate subsequent allogeneic HSCT. Keywords Acute lymphoblastic leukemia Adult Relapse Reinduction
Introduction While the cure rate of pediatric acute lymphoblastic leukemia (ALL) is approaching 90 % [1], the outcome of adult ALL drastically lags behind, primarily due to disease relapse, with less than half of the adults being cured and becoming long-term survivors [2, 3]. Adopting pediatricderived regimens in adult ALL have been proven to be feasible and effective [4, 5]. The prognosis of adult ALL patients who relapse or are refractory to induction therapy is dismal, and long-term survival is only around 10 % [6–9]. The primary purpose of salvage therapy in relapsed/refractory ALL is to achieve complete remission (CR) in order to subsequently perform allogeneic hematopoietic stem cell transplantation (HSCT) as soon as possible, given the fact that remissions beyond the first CR are universally not durable. Allogeneic HSCT is currently the only curative modality for refractory/ relapsed adult ALL, and the outcome of HSCT is superior when it is performed during remission rather than in patients with active leukemia [6]. Therefore, the challenge is to achieve a relatively durable second CR (CR2) with salvage therapy as a bridge to HSCT. With current salvage
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regimens, only around a third of relapsed/refractory adult ALL patients achieve CR2 or higher [6, 8, 10]. In an attempt to improve the CR rates of relapsed adult ALL patients and allow more patients to become candidates for HSCT, we designed a regimen modeled after the Berlin-Frankfurt-Muenster (BFM)-85 German Cooperative Group trial which proved to be highly effective in relapsed pediatric ALL [11]. The BFM-85 pediatric trial included induction with high-dose methotrexate and cytosine arabinoside, followed by post-remission therapy consisting of 2 alternating multi-agent treatment blocks and achieved in heavily pretreated children, a CR rate of 90 % with an event-free survival at 5 years of 30 %. We modified this pediatric protocol by adding a second induction cycle of continuous infusion of vincristine, adriamycin and dexamethasone (VAD) with ifosfamide in all patients regardless of whether they achieved a CR after the first cycle of induction therapy [12, 13]. Herein, we report the results of our prospective trial in adults with relapsed ALL as well as the outcome of a retrospective cohort treated subsequently.
Med Oncol (2013) 30:744 Table 1 Chemotherapy protocol (induction phase I and II) Induction phase I Allopurinol
300 mg/day PO days 1–15
Prednisone
100 mg/m2 PO days 1–8 and 15–21
Vincristine
1.5 mg/m2 (max 2 mg) intravenously (IV) on days 1, 8, 15 and 22
Cytarabine
3 g/m2 IV over 3 h bid for 4 doses on days 1 and 2
Methotrexate
1 g/m2 continuous IV infusion (CIV) over 36 h on day 15
Leucovorin
30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6 doses
L-Asparaginase
10,000 units/m2/dose IV on days 3, 4, 16 and 17
Filgrastim
5 mcg/kg/day SC injections were started 24 h after the end of cytosine arabinoside
Induction phase 2 Dexamethasone Ifosfamide
500 mg/m2/day IV on days 1–4
Mesna
500 mg/m2/day IV immediately before ifosfamide on days 1–4
Vincristine
0.4 mg/m2 (max 2 mg) CIV on days 1–4
Adriamycin
12 mg/m2 CIV on days 1–4
Filgrastim
Patients and methods Patients The phase II prospective study as well as the analysis of the retrospective data were approved by the Institutional Review Board of Keck School of Medicine of the University of Southern California. The eligibility criteria for the prospective study included patients with ALL who relapsed or were refractory to chemotherapy, age range of 17–55 years, Karnofsky performance status of [50 % and adequate hepatic and renal function. The diagnosis of relapsed ALL was based on bone marrow morphology and immunophenotypic analysis. Cytogenetic characterization was not required for study entry. Because of the intensity of our study regimen, we limited our study to adults younger than 55 years of age. Patients with central nervous system (CNS) involvement were eligible for this protocol if bone marrow was involved as well. Exclusion criteria were congestive heart failure or ejection fraction \45 %, other severe medical or psychiatric conditions, positive HIV test or known hypersensitivity to E coli-derived proteins. No patient had received high-dose cytosine arabinoside or high-dose methotrexate at any time prior to enrollment in this trial. Therapy The induction protocol is summarized in Table 1 and was mostly adapted from the BFM-85. It is consisted of two
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Starting on days 28–30 40 mg/day PO on days 1–4, 9 to 12
Intrathecal Therapy Methotrexate
5 mcg/kg/day SC injections were started on day 5 Prophylaxis starting on day 1 or 2 of phase II 12 mg on day 1 or 2
Cytosine arabinoside
30 mg on day 1 or 2
Hydrocortisone
15 mg on day 1 or 2
induction phases. The first phase included high-dose cytosine arabinoside followed 2 weeks later by high-dose methotrexate; E. Coli asparaginase was given for 2 days after each agent. The second induction phase was given irrespective of whether or not the patients achieved a CR and included VAD as reported by Kantarjian et al. [11–13] and intensified with addition of ifosfamide. Prophylactic filgrastim 5 mcg/kg/day was given 24 h after administration of each of the induction phases. Consolidation therapy consisted of alternating blocks of multi-agent chemotherapy for total of 8 cycles (4 cycles each block) (Table 2). Filgrastim 5 mcg/kg was administered daily in the consolidation blocks when the ANC was \0.5 9 109/L. Intrathecal (IT) prophylaxis was administered on days 1 or 2 of induction phase II and on day 8 of each consolidation block. If the CNS was involved prior to induction, IT therapy was administered twice weekly until CSF sterilization, then weekly for 1 month, followed by cranial radiotherapy with 18 cGy (if not given during first remission). After the eighth consolidation block, patients continued with maintenance chemotherapy (Table 2). In all treatment phases, except for the maintenance phase,
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Table 2 Chemotherapy protocol (consolidation and maintenance)
Table 3 Patient Characteristics
Consolidation block I Prednisone
100 mg/m2 PO days 1–5
6-Mercaptopurine
100 mg/m2/day PO on days 1–5 2
Vincristine
1.5 mg/m (max 2 mg) intravenously (IV) on day 1
Cytosine arabinoside
300 mg/m2 IV on day 1
VP-16
Prospective cohort
Retrospective cohort
Number of patients
19
31
Period of cohort enrollment
1993–1999
2004–2013
Median age, years (range)
25 (19–51)
36 (18–53)
Cell type, No
2
Precursor B cell
16
29
2
T cell
3
2
Median WBC at relapse (range), 109/L
13 (2–70.3)
5 (1.5–116)
Median previous CR duration, months (range)
10.5 (3–60)
16 (1–79)
1 (1)
1 (1–2)
19/0
28/3
100 mg/m /day PO on days 1 to 5
Methotrexate
500 mg/m IV infusion over 4 h on day 8
Leucovorin
30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6 doses
Filgrastim
5 mcg/kg/day SC injections if ANC \ 0.5 x 109/L until an ANC of C 10 x 109/L
Consolidation block II 6-Thioguanine
100 mg/m2/day PO on days 1–5
Dexamethasone
20 mg/m2/day PO on days 1–5
Ifosfamide
1.33 g/m2 IV on day 1
Median prior lines of therapy, No (range)
Mesna
1.33 g mg/m2 IV immediately before ifosfamide
Disease status
Vincristine
2
1.5 mg/m (max 2 mg) CIV on day 1 2
Methotrexate
500 mg/m IV infusion over 4 h on day 8
Leucovorin
30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6 doses 5 mcg/kg/day SC injections if ANC \ 0.5 9 109/ L until ANC of C 10 x 109/L
Filgrastim
The consolidation block I and block II are rotated for a total of 8 cycles (each block 4 times). Each block is given at intervals of 28 days provided ANC [1,000 and platelets are [75,0000 Intrathecal therapy
Prophylaxis starting on day 8 of block I and block II. If CNS involvement, then 2 times weekly until CSF sterilization. Then, IT therapy continued on a weekly basis for 1 month.
Maintenance therapy Methotrexate
50 mg/m2 PO once weekly for 2 years
6-Thioguanine
50 mg/m2 PO on daily basis for 2 years.
chemotherapy doses were not modified for hematological toxicity. Statistical considerations This was a pilot, phase II, single-institution, prospective clinical trial. The primary objective of the study was the CR rate after the two phases of induction therapy. Secondary objectives were LFS, regimen toxicity and number of days for until neutrophil count recovery after each cycle of induction. CR was determined by morphologic evaluation of the bone marrow on day 28 of induction and defined as cellularity greater than 20 %, maturation of all cell lines, less than 5 % marrow blasts, peripheral ANC [1.5 9 109/L and a platelet count of [100 9 109/L.
Relapsed/ refractory
Disease location at relapse BM only
19
23
BM ? CNS
5
Non-CNS extramedullary (± BM)
4
Cytogenetics [No]
Unavailable
Ph-positive [3], NK [18], del(9) [1], del(1) [1], der(11) [1], t(1;2) [1], unknown [6]
Previous chemotherapy
Unavailable
Modified BFM regimen = 25 Unknown = 6
BM bone marrow, CNS central nervous system
Relapse from CR was defined as the occurrence of any of the following: (1) greater than 5 % blasts in the bone marrow, not attributable to the regeneration of bone marrow following chemotherapy-induced aplasia, (2) reappearance of leukemic blasts in the peripheral blood or (3) biopsy-proven extramedullary leukemia. Treatment failure was defined as either resistant disease or persistence of bone marrow aplasia. Resistant disease was defined as the lack of CR in surviving patients despite receipt of both phases of induction therapy. All patients were considered eligible for response and toxicity assessment. Leukemia-free survival (LFS) was calculated from the time of CR to the time of relapse, last follow-up or death. Overall survival (OS) was calculated from the beginning of treatment to the time of death. The survival and remission duration curves were calculated using standard Kaplan–Meier methodology.
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Table 4 Outcomes
CR, N (%)
Prospective cohort
Retrospective cohort
13 (68 %)
16 (52 %)
Transplanted patients, N (%)
1 (5 %)
9 (29 %)
Refractory disease, N (%)
1 (5 %)
12 (39 %)
Death during induction, N (%)
5 (26 %)
3 (10 %)
OS (months)
5.6
16.1
Results Patient characteristics Fourteen men and 5 women were enrolled in our study between August 1993 and June 1999. Patient characteristics are shown in Table 3. The study was stopped due to slow patient accrual before the planned sample size of 25 patients was reached. Precursor B cell ALL was diagnosed in 16 patients, while three patients had T cell ALL. All patients had first relapse of ALL after a median of 10.5 (range, 3–60) months from initial diagnosis. The median age of patients was 25 years (range, 19–51). The median white blood cell count (WBC) at the time of relapse was 13 9 109/L (range, 2–70.3). Response to therapy The results of the induction therapy are summarized in Table 4. Thirteen of the 19 patients (68 %) achieved a CR (95 CI, 43–87 %). Of those 13, 11 (85 %) did so after receiving the initial phase of the induction therapy. The median time to CR from the start of the induction therapy was 28 days (range, 20–94). Of the 6 (31 %) patients who failed to achieve CR, 1 had primary refractory disease, while the others died of treatment-related infections or hemorrhage (including 2 died during first induction and 3 during second induction). Except for one, no patient underwent allogeneic HSCT. Reasons for inability to proceed to HSCT included early relapse, lack of suitable donor or socioeconomic reasons. All 13 patients who achieved CR proceeded to the postremission phase of the protocol. Only 7 patients completed between 1 and 3 consolidation blocks; no patients from the prospective cohort completed all of the consolidation blocks. The median OS of all 19 patients was 5.6 months (Fig. 1). However, the 13 patients who achieved CR had a median OS of 10.3 months. Eighteen of the 19 (95 %) study patients died during the course of the trial. The causes of death of the 18 patients were as follows: 11 from disease progression, 5 of infection, 1 of bleeding and 1 of unrelated causes. One patient underwent successful
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allogeneic BMT and become a long-term survivor. The median LFS was 4.3 months (Fig. 2). Hematologic recovery after chemotherapy and myelosuppression-associated complications All patients experienced severe bone marrow suppression with marked thrombocytopenia and neutropenia. Febrile episodes occurred in 18 patients. After induction therapy, 4 (21 %) patients died of documented infections and 1 patient died from bleeding during bone marrow aplasia (grade 5 toxicity). The median duration of recovery to ANC of greater than 0.5 9 109/L during the first induction phase was 21 days (range, 14–78) and to platelet count greater than 20 9 109/L was 28 days (range, 11–89). Non-hematologic toxicity No instances of grade 4 non-hematologic toxicity were observed (Fig. 3). The most common toxicity was grade 1 or 2 nausea/vomiting in 10 (53 %) of patients. Grade 3 liver toxicity was observed in 2 patients (11 %), while grade 1 or 2 liver toxicity was seen in 9 patients (47 %). Diarrhea of grade 1 or 2 occurred in 5 (26 %) of patients and grade 3 in only 1 (5 %) patient. Stomatitis occurred in 6 (31 %) patients and was grade 1 or 2 in 26 % of patients and grade 3 in 5 % of patients. Grade 1 or 2 skin rash was seen in 3 (16 %) patients. Outcomes of patients treated off the study Due to the slow accrual and lack of continuous funding, the study was closed prematurely after enrolling 19 patients. However, given the promising high rate of remission observed in the prospective trial and the absence of a standard approach, this regimen became our preferred salvage therapy for refractory/relapsed ALL. Subsequently, we retrospectively reviewed the outcome of a cohort of 43 consecutive patients treated with same regimen off study between 2004 and 2013, and a time period was chosen due to the availability of electronic medical records which made data review feasible. This analysis was limited to adult patients younger than 55 years with relapsed/refractory ALL who were treated with same regimen. However, we excluded from the analysis, cases with isolated CNS relapse as well as cases with insufficient data. Patients who did not achieve CR with the first cycle of salvage induction therapy were deemed refractory and allocated to different treatment in contrast to the prospective study where cycle two of induction therapy was administered prior to classifying the patient as refractory. Toxicity data were not collected due to the retrospective nature of the analysis.
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Fig. 1 OS. Prospective (left) and retrospective (right)
Fig. 2 LFS
pediatric-inspired intensive regimen (81 %) [14]. Of the 31 patients treated with this regimen, 16 (52 %) achieved CR, 3 (10 %) died during induction therapy with bone marrow aplasia and 12 (39 %) were refractory to induction therapy. Only 2 patients successfully completed all cycles of consolidation therapy and continued on the maintenance phase of the regimen. In all other patients in CR, the regimen was discontinued due to relapse or proceeding to HSCT. Nine patients subsequently underwent allogeneic HSCT. The median OS for patients included in the retrospective analysis was 16.1 months (Fig. 1). The pooled analysis for 50 patients (study = 19 and off study = 31), 29 (58 %) patients treated with this regimen achieved a CR and induction-related mortality of 16 %. The total number of patients who underwent allogeneic HSCT was 10.
Discussion
Fig. 3 Toxicities
Among the 43 patients who screened for retrospective analysis, 12 were excluded, and the reason of exclusion was as follows: 6 had only isolated CNS relapse, 4 were older than 55 years of age and 2 had insufficient data to confirm receiving the regimen. Therefore, only 31 patients were suitable for analysis, and the median age was 36 years. Patient characteristics are shown in Table 3. All of these patients were refractory or had relapsed following intensive first-line therapy, and the majority (97 %) of patients had received only one prior line of therapy, most commonly a
No standard salvage therapy exists for relapsed/refractory adult ALL. Various salvage regimens achieve CR in only a third of the patients with relapsed/refractory ALL, and leukemia resistance remains the leading cause of death in these patients, and it dwarfs the treatment-related mortality from any regimen [6, 8, 10]. The low CR rate for the current salvage regimens in adult ALL presents the main barrier for bridging patients to allogeneic HSCT. Achieving a durable CR is a key step for a successful HSCT, and it is one of the major limiting factors to performing HSCT besides donor availability and socioeconomic obstacles. In this study, we investigated the concept of intensive chemotherapy with high-dose methotrexate and cytosine arabinoside integrated with a continuous infusional regimen followed by alternating blocks of consolidation therapy. This concept was successfully applied in earlier pediatric studies and provided the impetus for our trial [11– 13]. Our aim in the study was to achieve a sufficiently durable second remission in relapsed adult ALL in order to render more patients candidates for HSCT and thereby be potentially cured.
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The main finding in this study was the remarkable high CR rate of 68 % in the prospective cohort which compares favorably with any salvage regimen for refractory/relapsed ALL. However, the CR rate was slightly lower in the retrospective cohort probably due to less stringent eligibility criteria as well as not mandating the second cycle of induction in patients who did not achieve CR with the first cycle in contrast to patients treated prospectively. In contrast to the prospectively treated patients, patients in the retrospective cohort were treated during a later time period and often had the exposure to more intensive prior therapy mainly an augmented pediatric-like regimen with highdose methotrexate and peg-asparaginase [14]. Of the 29 patients who achieved CR, only 10 (34 %) underwent allogeneic HSCT. The observed low transplant rate can be attributed to various socioeconomic barriers, availability of donor and disease relapsed before the transplant is ready. But the major obstacle was a timely availability of suitable donors for allogeneic HSCT during the time period during which this study was conducted. Nowadays, this would be a lesser a factor with the availability of a larger pool of matched unrelated donors and other alternate donor sources such as umbilical cord blood and haploidentical donors. Increased use of alternate donor sources particularly haploidentical donors should allow a majority of patients who achieve CR with this regimen to proceed to allogeneic HSCT. Therefore, despite short remission duration, the high CR rate achieved should allow more patients to receive an allogeneic HSCT. Transplant outcomes in the study could not be evaluated as our institution did not have an allogeneic program, and eligible patients were referred to other institutions for HSCT. In spite of the high CR rate seen in the study, the median LFS and OS of the prospective cohort were only 4.3 and 5.6 months, respectively, and these durations are in concordance with previous reports [7, 8, 10]. This is related to the low number of patients who underwent HSCT in CR2, as only one patient underwent HSCT in the prospective cohort and became a long-term survivor. In a retrospective analysis of 547 adults with relapsed ALL from the German Multicenter Study Group for Adult ALL (GMALL), none of the patients who had not undergone HSCT in CR2 became a long-term survivor, which highlights the crucial role of early HSCT in curing relapsed adult ALL [6]. Therefore, any salvage chemotherapy regimen can only be considered a bridge to allogeneic HSCT at the present time. Interestingly, the median OS was longer in the retrospective cohort, which might be related to more patients undergoing HSCT, variation in patients baseline characteristics (longer previous CR duration) and improved supportive care in the more recent years of treatment (2000s vs. 1990s).
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Our unusually high CR rate of 68 % and especially the low rate of disease resistance could be related to various factors including (1) an intense induction therapy regimen that included high-dose cytosine arabinoside and methotrexate in patients who had mostly not received prior high doses of these agents. (2) The sequencing of L-asparaginase when given immediately following high doses of methotrexate or cytosine arabinoside (with so called ‘‘Capizzi effect’’), which has previously shown to induce CR rates of half of the patients with relapsed disease [11, 15]; and (3) the relatively young age of the patients in our study. Our regimen may be of special benefit to the relapsed adult ALL patients who have not already received multiple doses high doses of cytosine arabinoside plus methotrexate, for example in those who had received the commonly used hyper-CVAD front line regimen. Sixteen percent of all patients died during induction therapy, which is in the range of other reports [10, 16]. Although hematological toxicities were common, nonhematological toxicities were manageable with no grade 4 toxicity and infrequent grade 3 toxicities observed in the prospective cohort. The consolidation phase of this regimen is also safe with acceptable non-hematologic toxicity, and it is mainly administered in the outpatient setting. However, it was not able to maintain a durable remission, which is in line with the known short second CR in adult ALL patients who are treated with chemotherapy alone. Salvage therapy for relapsed refractory ALL is evolving with development of active novel targeted agents [17]. Our regimen could serve as a back bone chemotherapy regimen for incorporation of these novel agents in order to further improve CR rates thereby improving the dismal long-term outcome of adult patients with relapsed/refractory ALL. Acknowledgments This work was partially supported in part by a grant from Amgen Inc. Conflict of interest
All authors disclose no conflict of interest.
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