Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400–600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.
The bcr-abl tyrosine kinase inhibitor imatinib mesylate has a significant but brief antileukemic activity in lymphoid blast crisis (LBC) chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). In phase I and II trials, imatinib monotherapy after conventional treatment in relapsed or refractory patients yields 20% of complete hematologic responses (CHR), but relapses occur in more than 85% of patients after a median duration of treatment of only 2–3 months.1, 2 These results are consistent with the rapid development of resistance to imatinib observed in advanced phase CML patients.3, 4, 5, 6
Several lines of evidence suggest that dose escalation may increase the antileukemic activity of imatinib. In newly diagnosed chronic phase (CP)-CML, high-dose imatinib induces higher rates of cytogenetic and molecular responses than standard-doses.7 In CP-CML patients with relapse or refractoriness to standard-doses imatinib, increasing the imatinib dosage brings a significant proportion of patients into response.8 In accelerated-phase CML, responses to imatinib are dose-dependent.9 Thus, high-dose imatinib may overcome resistance mechanisms such as amplification of the bcr-abl gene and mutations outside the ATP-binding site of abl in LBC and Ph+ ALL, but this strategy has not yet been explored.
An alternative to increase imatinib efficacy and to bypass resistance may reside in upfront combination therapy with standard cytotoxic agents. Others have described a synergistic or additive activity of imatinib with other antileukemic agents.10 In de novo or refractory Ph+ ALL, the hyper-CVAD regimen together with imatinib at 400 mg daily from day 1–14 of each chemotherapy cycle provides encouraging results with a 100% CRH rate.11 High CHR rates are also achieved in newly diagnosed Ph+ ALL using imatinib at 600 mg daily together with an intensive four drugs-based induction chemotherapy.12, 13
Here, we report the results of a multicenter pilot study designed to evaluate the clinical efficacy and the tolerance of high-dose imatinib associated with a nonintensive sequential vincristine and dexamethasone chemotherapy schedule (Dexamethasone, Imatinib and Vincristine, DIV regimen) in a series of 31 patients with LBC and relapsed or resistant Ph+ ALL.
Patients and methods
Patients with a confirmed diagnosis of LBC and Ph+ ALL were included in this pilot study after informed consent, whether previously treated or not with imatinib. For patients with CML, LBC was defined as more than 30% lymphoblasts in blood or bone marrow irrespective of prior therapy. For patients with Ph+ ALL, relapsed disease was defined as first relapse after standard induction chemotherapy or allogeneic stem cell transplantation. Ph+ ALL patients were considered as resistant/refractory to chemotherapy if bone marrow lymphoblasts persisted at day 8 of conventional induction chemotherapy or if they failed to obtain CHR after one or two induction chemotherapy courses.14 Patients were required to have an ECOG performance status 0–2, a serum creatinine less than 176 μmol/l, hepatic transaminases and bilirubin less than threefold normal range, no central nervous system (CNS) involvement and no uncontrolled severe infection.
Study design and treatment
Treatment consisted in a unique induction course where imatinib was administered at 800 mg per day (400 mg twice daily) until hematological recovery for a maximum of 56 days, together with 2 mg vincristine intravenously on days 1, 8, 15 and 22 and 40 mg dexamethasone either orally or intravenously on days 1–2, 8–9, 15–16 and 22–23. CNS prophylaxis consisted in four intrathecal injections of 15 mg methotrexate, 40 mg cytosine arabinoside and 40 mg dexamethasone on days 1, 8, 15 and 22. Imatinib treatment was interrupted or reduced from 800 to 600 mg per day in case of grade 3–4 nonhematological toxicity according to National Cancer Institute/National Institutes of Health Common Toxicity Criteria. Vincristine was switched to vindesine (4 mg per injection) or etoposide (100 mg per injection) in case of grade 3 or higher peripheral neuropathy. No dose reduction was planned for hematological toxicity until day 56. The management of tumor lysis syndrome was performed under the guidelines of each participating center. Prophylactic antibiotherapy with trimethoprim-sulfamethoxazole and valaciclovir was recommended for all patients.
Evaluation and criteria for response
Hematologic, cytogenetic and molecular evaluations were programmed upon hematological recovery between days 28 and 35. In the absence of hematological recovery, a bone marrow aspiration was performed systematically at day 56 to assess the presence or the absence of residual lymphoblasts. CHR was defined as follows: 5% or less blasts in a normocellular or hypercellular marrow with peripheral granulocyte counts of at least 1.0 × 109/l and platelets counts of 100 × 109/l or higher. Cytogenetic responses were defined as follows: complete, Ph 0%; partial, Ph 1–34%; minor; Ph 35–90%. Major cytogenetic responses included complete and partial responses. Bcr-abl transcripts were quantified in blood and bone marrow by RQ-PCR.15 Complete molecular remission was defined by the absence of detection of bcr-abl transcript with a sensitivity of 10−5.
Differences in hematological response rate and level of molecular response by pretreatment characteristics among subgroups were, respectively, analyzed by Fisher exact test and Mann–Whitney. Kaplan Meier survival analysis was performed to estimate disease-free survival (DFS) and overall survival (OS) and differences between subgroups were analyzed by the log rank test. Statview 5.0 (SAS Institute, Cary, NC, USA) was used for all statistical analysis.
Results and discussion
A total of 31 patients including 18 Ph+ ALL and 13 LBC were enrolled from September 2001 to September 2004. Patients’ characteristics are listed in Table 1. Of the 31 patients including one patient not assessable because of early death during induction, 28 (90%) achieved a CHR, among which 17/18 with relapsed or resistant Ph+ ALL (94%) and 11/13 with LBC (84%). The median time to CHR was 33.5 days (range, 20–68). Twenty-four patients (15 Ph+ ALL and nine LBC) had not been previously treated with imatinib and 22 of them (15 Ph+ ALL and seven LBC) achieved a CHR (91%). Seven patients (three Ph+ ALL and four LBC) had previously received imatinib and six of them (two Ph+ ALL and four LBC) had a CHR (84%). Of note, the Ph+ ALL patient who failed to respond had acquired resistance to imatinib since a single point mutation E255K was identified prior initiation of treatment. The differences in CHR rates according to previous imatinib exposure were not statistically significant in our study.
Cytogenetic evaluation at the time of CHR was performed in 20 patients (11 Ph+ ALL and nine LBC). Major cytogenetic responses were obtained in 16 patients (10 Ph+ ALL and six LBC) including 14 complete responses and two partial responses. Minor cytogenetic responses were observed in two LBC patients. Two patients did not show any cytogenetic response among which one LBC and one Ph+ ALL patients, both with previous exposure to imatinib, the latter patient even showing clonal evolution.
The evaluation of the molecular response at the time of CHR was performed in 24 patients (15 Ph+ ALL and nine LBC). A rapid decrease in bcr-abl transcripts was observed with a median bcr-abl/abl ratio of 0.001 (range, 0–0.09). Remarkably, one patient with Ph+ ALL and one patient with LBC achieved complete molecular remission. Median bcr-abl/abl ratio was measured at 0.0005 (range 0–0.02) in Ph+ ALL and at 0.008 (range, 0–0.09) in LBC. Bcr-abl/abl ratio was significantly lower in patients without previous imatinib treatment (median 0.00075; range, 0–0.09; 14 Ph+ ALL and 6 LBC) than in patients previously exposed to imatinib (median 0.014; range, 0.02–0.006; four LBC) (P=0.025). These results suggest a deleterious effect of previous imatinib exposure on molecular responses among patients in our study.
Hematological toxicity of the DIV induction therapy compares favorably to that reported in protocols using high-dose chemotherapy combined with imatinib.11, 12, 13 Median time to neutrophil recovery of at least 1.109/l was 21 days (range, 1–43) and median time to platelet recovery of at least 50.109/l was 16 days (range, 1–65).
The incidence of documented infections was 32% (10/31) comprising three disseminated candidiasis, three pulmonary aspergillosis including two recurrences, three bacterial sepsis and one herpetic encephalitis. One patient died of systemic candidiasis and staphylococcal septicemia on day 35 of induction. Grades 2–3 neuropathy due to vincristine occurred in 14 cases (45%) and lead to the replacement of vincristine by vindesine or vepeside in nine cases. Other, more than grade 2 nonhematological toxicity was rare (three grade 3 nausea, two grade 3 and four hepatopathy, one grade 3/4 fluid retention, one grade 3 reversible pulmonary fibrosis, one grade 4 oral mucitis and one acute subdural hematoma). One patient had reduction in the doses of imatinib from 800 to 600 mg per day owing to grade 3 nausea. Three patients temporarily discontinued imatinib owing to severe pancytopenia (n=1), fluid retention (n=1) and nausea (n=1).
After induction with the DIV regimen, patients in CHR received varying consolidation treatments including allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n=9), bcr-abl-negative autologous stem cell graft (n=1), imatinib alone (n=1), imatinib in combination with donor lymphocyte infusion (n=2) or imatinib associated to corticosteroids or chemotherapy (n=15). Of note, allo-HSCT was performed after a median time of 78 days post-CHR (21–233). After a median follow-up of 256 days (28–1049), 64.5% (20/31) of patients remain alive including 19 with persistent CHR and one that failed to reach CHR. Eleven patients have died, one of infection before the end of the induction regimen, one owing to refractory disease, seven owing to relapse and one of graft-versus-host disease 375 days after allo-HSCT. The median length of OS was 404 days (Figure 1a).
We determined whether exposure to imatinib prior DIV induction had an impact on survival and we found a trend for an longer OS in patients without previous imatinib treatment (448 days) than in those with previous imatinib intake (222 days) although this difference did not reach statistical significance (P=0.12 by the log-rank test). For patients who achieved CHR, median length of DFS was 288 days (Figure 1b) and a significant difference according to previous imatinib exposure was found since the median length of DFS in patients without and with previous imatinib treatment was, respectively, 140 and 476 days (P=0.02 by the log-rank test) (Figure 1c).
When analyzing the possible effect of age on DFS and survival, we did not observed any significant differences between patients aged under 55 years and over 55 years when patients were censored for hematopoietic stem cell transplantation (Figure 1d). The rate of complete remission (CR) was 90% in patients over 55 years and 95% in younger patients which was also not statistically significant. This indicates that the DIV regiment is also effective in aged patients and well tolerated in our experience.
In conclusion, the DIV regimen induces high CHR rates, even in patients heavily treated and allows major molecular responses within the first month of treatment. These results compare favorably with those reported in de novo Ph+ ALL by Thomas et al.11, Towatari et al.12 and Lee et al.13, where more intensive chemotherapy and lower doses of imatinib were used. Furthermore, a high proportion of patients (nine out of 19 patients under 55 years) have been allografted including all patients with an HLA identical donor identified before salvage therapy. The point that patients over 55 years achieved the same rate of CR than younger patients may indicate that such an imatinib-based induction without high-dose therapy may be recommended for aged patients. This question will be asked in a future European study comparing an imatinib-based induction regimen to intensive chemotherapy plus imatinib. The recent observation that exposure to genotoxic agents may favor further emergence of BCR-ABL tyrosine kinase domain mutations under imatinib therapy may also influence the choice of molecules not involved in DNA repair or mutations in combination with imatinib in imatinib-naïve patients.16
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Rea, D., Legros, L., Raffoux, E. et al. High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia. Leukemia 20, 400–403 (2006). https://doi.org/10.1038/sj.leu.2404115
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