Continuous Infusion Cytarabine Research Articles

Treatment of Elderly Acute Myeloid Leukemia Patients

Older patients with acute myelogenous leukemia (AML) fare much less well than younger patients with the same disease due to a combination of comorbidities and intrinsic disease resistance. Likely due to aging of the US population, the median age of AML patients at diagnosis has increased from 68 to 72years. AML is a heterogeneous disease, particularly in older patients, making therapeutic decisions challenging. Older patients who are 'fit' for intensive chemotherapy and would have a reasonable chance to benefit based on host and disease characteristics should receive standard induction chemotherapy with 7days of continuous infusion of cytarabine and at least 60mg/m(2) daunorubicin daily for 3days. Therapeutic options for patients who are not candidates for or are not likely to respond to intensive therapy include clofarabine, low intensity chemotherapy such as low dose cytarabine, hypomethylating agents, or investigational agents. For older AML patients in complete remission, post-remission or consolidation chemotherapy with repeat induction or modified high dose cytarabine may offer a small chance for long term disease-free survival. Selected older patients who achieve remission by any means should be considered for reduced-intensity stem cell transplantation which may offer improved chances of cure and survival compared with standard post-remission chemotherapy.

Empiric Antifungal Therapy with Amphotericin B in the Era of Fluconazole Prophylaxis: a Cohort Study in Adults with Acute Myeloid Leukemia Treated within An Institutional Antifungal Policy.

Abstract 1390Poster Board I-412 Purpose:To determine whether fluconazole prophylaxis was effective in decreasing the need for parenteral empiric antifungal therapy in patients with acute myeloid leukemia (AML) and persistent febrile neutropenia or suspected fungal infection at our center. Background:Prophylaxis with fluconazole in patients with severe chemotherapy-related neutropenia has been found to be beneficial in decreasing the need for parenteral antifungal therapy, and preventing superficial and invasive fungal infections and fungal infection-related mortality (Bow et al., Cancer 2002;94:3230-3246). Methods:The records of all patients at our hospital who presented with AML from January 1999 to July 2009 were reviewed retrospectively. As of September 2005 we adopted an institutional antifungal policy consisting of routine antifungal prophylaxis with fluconazole followed by amphotericin B as the first line parenteral agent in the event of persistent fever despite broad spectrum antibiotics or suspected fungal infection. The policy included criteria for switching from amphotericin B to a second line agent (caspofungin) for continued empiric therapy or another agent depending on clinical or laboratory data or suspicion of a particular pathogen. Explicit criteria were also developed for switching to a second line agent including baseline renal function or change in renal function while receiving amphotericin B or other adverse effects such as significant infusion reactions or electrolyte disturbances. Fluconazole was given at a dose of 400 mg daily starting with induction chemotherapy and continued until blood count recovery or switch to parenteral antifungal agent. Results:We identified a total of 170 patients with a median age of 61 years (range 18-89 years), 53 % were female and the median follow-up time was 187 days (range 2-2549 days). Baseline cytogenetics grouped patients into poor risk (40%), standard risk (39%) and favorable risk (10%) categories, with 11% unknown or inconclusive. Two-thirds of patients had de-novo AML. Twenty-four percent of patients did not receive induction chemotherapy and were treated with best supportive care, leaving 130 patients who received induction chemotherapy. Overall median survival for chemotherapy treated patients was 409 days, compared with 44 days for patients treated with best supportive care. The majority of patients (77%) who received chemotherapy were treated with standard induction consisting of 3 days of an anthracycline and 7-10 days of continuous infusion cytarabine. Of the patients treated with induction chemotherapy, 65% received prophylaxis with fluconazole and 32% did not, the remainder received prophylaxis with other antifungal agents. The use of prophylactic fluconazole coincided with implementation of our antifungal policy. Of patients who were treated with fluconazole prophylaxis, 62% required parenteral antifungal therapy and 38% did not. Of patients who did not receive fluconazole prophylaxis 56% required parenteral antifungals and 44% did not. These differences relating to receiving fluconazole prophylaxis were not statistically significantly different. For those patients requiring empiric antifungal therapy, they received a median of 18 days of fluconazole (range 3-156 days). Of the 56 patients who were treated with amphotericin B as empiric therapy, 59% were changed to another agent due to renal effects (42%), fever (27%) or other adverse effects (21%). Switching off amphotericin B occurred after a median of 7.5 days (range 0-59 days). Fifty-six percent of patients received caspofungin as the second line agent while the policy was in effect. Conclusion:Based on our retrospective analysis of the practical use of antifungal prophylaxis within our institutional antifungal policy, fluconazole prophylaxis did not decrease the need for empiric parenteral antifungal therapy. The majority of patients treated with empiric amphotericin B were switched to a second line agent, mostly due to intolerance or adverse effects. Disclosures:No relevant conflicts of interest to declare.

Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse

AbstractLaromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m2 per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m2 (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.

Combination of cladribine and cytarabine is effective for childhood acute myeloid leukemia: results of the St Jude AML97 trial

Because cladribine can increase cytarabine triphosphate levels, we tested a cladribine—cytarabine combination in the St. Jude AML97, trial in which this combination was administered before standard chemotherapy to 96 children with acute myeloid leukemia (AML) or myelodysplastic syndrome. Patients received a 5-day course of cladribine (9 mg/m2/dose) and cytarabine either as daily 2-hour infusions (500 mg/m2/dose) (arm A) or a continuous infusion (500 mg/m2/day) (arm B). Ara-CTP levels and inhibition of DNA synthesis increased from day 1 to day 2, but were not different between the two arms. In addition, the median blast percentages at day 15 did not differ between arms A and B, but patients treated in arm A had shorter intervals between the initiation of the first and second courses of therapy. Thus, although there were trends towards better CR rates and overall survival for patients treated in arm B, the reduced efficacy of arm A may have been partially compensated by more intense timing of therapy for that group. For all patients, 5-yr event-free survival and overall survival estimates were 44.1% ± 5.4 % and 50.0% ± 5.5%. Our results suggest that cladribine in combination with continuous-infusion cytarabine is effective therapy for childhood AML.

Voreloxin (formerly known as SNS-595) in Combination with Cytarabine Demonstrates Preliminary Clinical Responses in a Phase 1 Study in Relapsed/Refractory Acute Myeloid Leukemia.

Background: Voreloxin (formerly SNS-595) is a first-in-class replication-dependent DNA damaging agent that causes apoptosis by DNA intercalation and inhibition of topoisomerase II. A previous phase 1 study of single-agent voreloxin demonstrated acceptable safety and strong signs of clinical activity in patients with relapsed/refractory hematologic malignancies (ASH 2007), where MTD was found to be 72 mg/m2 weekly x 3 and 40 mg/m2 twice weekly x 4. In nonclinical models, the combination of voreloxin and cytarabine demonstrated enhanced activity. Preliminary results of an ongoing phase 1b study of combination voreloxin plus cytarabine in relapsed/refractory AML patients are reported.Objectives:establish safety, tolerability and MTD of escalating doses of voreloxin combination with continuous infusion cytarabine,characterize voreloxin PK in the setting of cytarabine given as a continuous intravenous infusion (CIV)assess clinical activityexplore markers of patient responseevaluate ex vivo voreloxin sensitivity in bone marrow as a predictor of response.Methods: Open label, doseescalation phase 1b study with a starting dose of voreloxin of 10 mg/m2 (given on days 1,4) in combination with 400 mg/m2/day CIV cytarabine for five days. Dose-limiting toxicities (DLTs) were assessed during cycle 1. PK analyses for voreloxin were performed during cycle 1. Pre- and post-dose PBMC were obtained to evaluate modulation of DNA damage response markers as correlates of patient response. Ex vivo sensitivity to voreloxin of baseline bone marrow samples was evaluated using the CellTiter-Glo® proliferation assay. Clinical response was determined based on IWG criteria. Patients could receive up to 2 courses of induction, and patients achieving CR or CRp could receive up to 2 courses as consolidation. At MTD, an additional cohort of patients will be enrolled to further assess safety.Results: To date, 26 patients have been enrolled and 24 have received treatment. Demographics: 16 males, 8 females, median age 61.4 years (range 30 – 74.5 yrs). Disease status: 17 of 24 treated patients had relapsed disease. Median number of prior therapies was 2 (Range 0–4). Two patients had prior allogeneic stem cell transplant. Dose escalation has proceeded to 80 mg/m2/dose (cohort 6). Safety: a single DLT has been observed (grade 5 septic shock in one patient treated at 70 mg/m2). Grade 3+ related non hematologic AEs ≥ 5% incidence: infections (23%). Grade 3+ hematologic toxicities have been consistent with past experience and include febrile neutropenia, anemia, and thrombocytopenia. The most common reason for early study termination was disease progression. Voreloxin pharmacokinetics were unaffected by cytarabine compared with the single agent phase 1 study. Preliminary clinical responses are listed below in Table 1.Conclusion: Voreloxin given in combination with continuous infusion cytarabine is generally well-tolerated, with encouraging signs of activity in patients with relapsed/refractory AML. Dose escalation continues.Table 1: Clinical Responses by CohortCohortVoreloxin DoseTreated/EnrolledDLTsResponses1104/4002203/401 CR3344/402 CR4506/602 CR5707/812 CR

Gemtuzumab Ozogamicin (GO) and Continuous Infusion Cytarabine (ARA-C) for Relapsed/Refractory Acute Myeloid Leukemia (AML) Prior to Allogeneic Stem Cell Transplantation (SCT).

The question whether to re-induce AML patients (pts) in first or subsequent relapse to reduce leukemia disease burden prior to SCT is not well studied. Several groups reported a 28–30% disease-free survival rate at five years for matched related donor SCT in first relapse without re-induction. Finally, re-induction regimen choices prior to SCT are relatively limited. Specifically, GO-containing regimens have been suspected to be associated with increased incidence of liver sinusoidal occlusive syndrome (SOS) when used prior to SCT. We evaluated our institutional experience of using GO and ARA-C for relapsed/refractory CD33-positive AML pts prior to allogeneic SCT. A total of 18 pts (median age 45.4 years; range 28–66) with relapsed/refractory AML were treated with GO/ARA-C. The median initial complete remission duration was 4.4 (range 0.5–14.5) months. The median time from relapse to GO/ ARA-C was 57 (range 6–142) days. Pts received GO (6 mg/m2 on day 1, 4 mg/m2 on day 8) and continuous infusion ARA-C (100 mg/m2) daily for 7 days. Bone marrow aspiration and biopsy were performed at a median of 15 (range 11–39) days post induction (one pt had >20% peripheral blasts on day 14 and therefore did not undergo bone marrow aspiration and biopsy). Three (17%) pts developed infectious complications following re-induction and one pt had disease progression that prevented them from undergoing bone marrow aspiration and biopsy and continuing on to SCT. Marrow aplasia (defined as <5% blasts and <20% cellularity) was reached in six of 14 (43%) evaluable pts. Three pts (all without achieving marrow aplasia) developed infectious complications that precluded SCT. A total of 11 pts proceeded onto SCT at a median of 30 (range 21–73) days after re-induction, including six pts who achieved marrow aplasia and five who did not. Six pts underwent matched unrelated donor SCT (two were mismatched at one allele) and five received matched sibling SCT. Reduced intensity preparatory regimens (fludarabine/melphalan) were used in all but one pt who received a fully myeloablative regimen (busulfan/cyclophosphamide). Engraftment to absolute neutrophil count ≥0.5x109/L for three days was achieved in all 11 pts at a median of 15 (range 9–21) days. During SCT, all pts were treated with prophylactic enoxaparin 40 mg subcutaneously once daily to prevent SOS of the liver. The two pts with mismatched unrelated donor SCT died three and nine days after achieving count recovery from pulmonary infiltrates and severe graft versus host disease (GVHD), respectively. Acute GVHD grade II-IV developed in six of the pts with matched donors (three related and three unrelated donors). Chronic GVHD developed in four (one related and three unrelated donors) of the pts. None developed liver SOS. Four pts are alive from starting GO/ARA-C at a median of 7.2 (range 1.2–52.7) months; two of them with and two of them without GVHD. Marrow aplasia prior to SCT was achieved in two of them. In summary, the question of whether to re-induce pts with relapsed/refractory AML to reduce leukemia burden prior to allogeneic SCT remains controversial. However, if one chooses to proceed with re-induction, then the combination of GO/ARA-C represents a feasible re-induction strategy with acceptable toxicity, achievement of marrow aplasia in approximately half of evaluable pts, and no increased risk of liver SOS in the setting of enoxaparin prophylaxis and low intensity conditioning regimens.

Secondary Acute Myeloid Leukemia (sAML) Treated with Amonafide (AS1413) + Cytarabine: Durable Responses in Poor-Risk AML

Background: Secondary acute myeloid leukemia (sAML), evolving from prior MDS or leukemogenic therapy (tAML), is associated with a poor prognosis. Many sAML patients are elderly with significant comorbidities. The incidence of unfavorable cytogenetics and expression of multidrug resistance (MDR) phenotype is higher in sAML blasts. Amonafide (AS1413) is a DNA intercalating agent and unique topoisomerase II (Topo II) inhibitor that, unlike the classical Topo II inhibitors (DNR, IDA, mitoxantrone, etoposide), does not affect the DNA/Topo II cleavable complex that results in DNA fragmentation. It does not act as either a substrate or an inhibitor of the MDR efflux pump, P-glycoprotein (Pgp), nor is it cross-resistant with classical Topo II inhibitors. A complete remission (CR) rate of 38.6%, with an additional 3.4% of patients achieving CRp, has previously been reported for this phase II trial. Updated findings from this trial including duration of remission data are reported here.Methods: Patients received a 4 hr infusion of amonafide 600 mg/m2/day × 5 and continuous IV infusion cytarabine 200 mg/m2/day × 7. 14 patients received a second course on day 14 for persistent leukemia. Patients received consolidation with stem cell transplant or intermediate/high dose cytarabine, depending on age. Central bone marrow review was performed for patients in CR. The primary endpoint was CR + CRp. Secondary endpoints included duration of CR/CRp. The last patient was treated in December 2006.Results: 88 patients were enrolled; median age was 62.5 (range 23–87); prior MDS, 48.9%, (43/88); tAML, 51.1% (45/88); unfavourable cytogenetics, 46.6% (41/88). The most common non-hematologic grade ≥ 3 AEs seen were febrile neutropenia (35.2%), hypotension (15.9%), pneumonia (14.8%), hypokalemia (12.5%), and bacteremia (11.4%). Death rate within 28 days was 20.5%. Overall CR + CRp rate: 42.0% (37/88), including 38.6% (34/88) CR; 3.4% (3/88) CRp. CR by age < 60: 39.4% (13/33); ≥ 60: 43.6% (24/55). 30/37 patients received post-remission therapy with BMT (7), high/intermediate dose cytarabine (21) or both (2).Kaplan-Meier estimate of the proportion of responders in continuous CR/CRp at 18 months is 41% for all sAML patients, and is similar for all poor-risk subgroups including age ≥ 60, 43%; tAML, 57%; and unfavorable cytogenetics, 38%. Median overall survival is 209 days for all patients and 400 days for patients with CR/CRp.Conclusions: Durable CRs have been achieved in patients with sAML/tAML treated with amonafide plus cytarabine. This efficacy was similar across subgroups independent of age or the presence of various poor risk characteristics. Phase III evaluation of amonafide plus cytarabine vs. daunorubicin plus cytarabine (3+7) is currently underway. [Display omitted]

Tolerability of An Effective Two Day Induction Regimen for Newly Diagnosed AML

Background: The standard remission induction regimen for treating Acute Myeloid Leukemia consists of seven days of continuous infusion cytarabine and three days of an anthracycline, the “7 + 3” regimen. We present a single institution, retrospective analysis of toxicity associated with a regimen that requires only two days of chemotherapy using high dose cytarabine and mitoxantrone. The regimen is based on the timed sequential therapy concept where two pulses of chemotherapy are given. The first pulse recruits cells into the cell cycle, while the second pulse is given at the time of peak recruitment.Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day of chemotherapy consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Each patient's chart and electronic record were thoroughly reviewed, and toxicities associated with induction therapy were analyzed and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0. Responses were defined per the Revised IWG Recommendations (Cheson, J Clin Onc 21: 4642, 2003).Results: One hundred four patients were eligible for toxicity evaluation. Hematologic toxicities were the most common toxicities seen with this induction therapy. Overall, all patients experienced hematologic toxicity of some grade with 98% of patients having one or more Grade 3/4 hematologic toxicity. The incidences of grade 3/4 hematologic toxicities are the following: Hemoglobin 65.3% (Gr 3 59.6%, Gr 4 5.7%), thrombocytopenia 93.2% (Gr 3 9.6%, Gr 4 83.6%), and neutropenia 89.4% (Gr 3 1.9%, Gr 4 87.5%). Febrile neutropenia occurred in 64% of the patients, and grade 3 and 4 infections occurred in 25%. Common non-hematologic toxicities included fatigue, nausea, vomiting, diarrhea, and electrolyte abnormalities. The vast majority of non-hematologic toxicities were grade 1 and 2. Three patients (2.9%) died within the first 30 days of induction therapy. One patient died before completing therapy due to massive hemoptysis. One died from complications of refractory disease, and the third patient died from disseminated fungal infection. An additional 10 patients (6 TF-RD, 1 TF-aplasia, 1 CR, 1 CRi, 1 CRp) died within the first 60 days. Of the 6 patients with refractory disease, 4 received re-induction therapy to which 3 did not have a response and the fourth died of sepsis while aplastic. Two patients had intracerebral hemorrhage (TF-aplasia and CRp). One patient died suddenly in CR of unknown causes and one patient (CRi) died from complications of pneumonia/ARDS.Conclusion: Although this regimen incorporating high dose cytarabine into remission induction presents a significantly higher dose intensity of cytarabine and mitoxantrone compared to that of the “7+3” regimen, the toxicity profile and 30-day mortality rate compare favorably to the “7 + 3” regimen. This regimen has been shown to produce a CR rate comparable to that of the “7+3” regimen with equal efficacy and better tolerance in elderly patients with AML. We conclude that this regimen effectively administers a high yet apt dosage of chemotherapy, and it can even be used for remission induction in elderly patients. This induction regimen could serve as a platform for future studies of maintenance and biologic therapies in the elderly AML patients.

Relapsed acute megakaryoblastic leukemia in Down syndrome (AMKL-DS) may be cured with chemotherapy alone, without stem cell transplantation (HSCT)

17543 Background: Children with recurrent AMKL -DS have an extremely poor prognosis without HSCT. Methods: We report a case of a relapsed AMKL-DS cured with intensive chemotherapy alone, without HSCT. Results: A 19 month old boy with Down syndrome, who had transient leukemia as a newborn, developed AMKL-DS (GATA1 positive) and was treated with four cycles of CI-TAD: continuous infusion of cytarabine and daunorubicin, and oral thioguanine for four days, and intrathecal cytarabine; followed by two cycles of high dose cytarabine plus L-Asparaginase; and three weekly doses of intrathecal cytarabine. Although he achieved remission at the completion of first cycle of the induction chemotherapy, he relapsed within 6 weeks after the completion of therapy. He then received the following chemotherapy over the next six months: Cycle 1 and 2. High dose Ara-C ( 33. 3 mg/kg q 12 hours x 8 doses) on days 0 to 3 plus mitoxantrone 0. 4 mg/kg/day x 4 on days 3 to 6 Cycle 3. High dose Ara-C 33. 3 mg/kg q 12 hours x 8 doses Cycle 4 and 5 (FLAG): Fludarabine 0. 8 mg/kg/day x 4 plus Ara-C 67 mg/kg/d x 4 and G-CSF 10 mcg/kg/day x 4 all on days 0 to 3. He achieved complete remission after the 1st cycle of chemotherapy, and underwent further cycles of chemotherapy while waiting for HSCT from an unrelated donor. But after the 5th cycle of chemotherapy, he developed a pulmonary lesion of fungal etiology for which he received three months of therapy with liposomal amphotericin. Because of a persistent lung lesion on imaging, he was considered ineligible for HSCT, and no further therapy was given. His bone marrow aspirate after the 3rd cycle of therapy was negative for GATA1. He has been disease-free for 59 months after the completion of his last cycle of chemotherapy, and he is currently in good health without any evidence of pulmonary or cardiac dysfunction. Conclusions: Intensive chemotherapy alone, without HSCT, may be curative for relapsed AMKL- DS. No significant financial relationships to disclose.

A Phase I Study of Oral 6-Thioguanine, Followed by Continuous Infusion Cytarabine, Followed by Intramuscular PEG-Asparaginase (“TGAP”) in Children with Relapsed or Refractory Acute Leukemia or Non-Hodgkin's Lymphoma.

Background: We found enhanced cytotoxicity against human leukemia cell lines resistant to cytarabine with the sequence specific three-drug combination, 6-thioguanine (6TG) + cytarabine + PEG-asparaginase (“TGAP”) [Fu et al, Cancer Chemother Pharmacol 48:123–133, 2001] and developed a Phase I study to evaluate TGAP's feasibility in children with relapsed/refractory leukemia or non-Hodgkin's lymphoma with marrow involvement.Patients and Methods: Three days of twice daily 6TG was followed by cytarabine @ 487 mg/m2 loading dose and 126 mg/m2/hr by 72-hour continuous infusion. Cytarabine was followed by pegylated asparaginase @ 2,500 units/m2. Complete response (CR) required fewer than 5% marrow blasts with recovery of neutrophils and platelets. Partial response required marrow blasts between 5% and 25% with no peripheral blasts.Results: Between April 1999-January 2006, 11 patients, age 1 to 18 years, were enrolled after local IRB approval and individual or parental informed consent. Six patients had relapsed/refractory ALL, 4 patients had relapsed ANLL (2/4 had Down syndrome) and 1 patient had relapsed Burkitt's lymphoma/leukemia. Six patients were enrolled at dose level #1 (6TG @ 100mg/m2/dose) and 5 patients were enrolled at dose level #2 (6-TG @ 150mg/m2/dose). The last patient enrolled was later found ineligible, but was included for toxicity. Chemotherapy was well tolerated in 9 patients. All patients developed grade 3–4 neutropenic fevers or bacteremia. Other grade 3–4 toxicities included transient elevations in transaminases. Asparaginase related pancreatitis occurred in two patients, in one with symptoms. Dose limiting acute vascular leak syndrome occurred in two patients at dose level #2 during the cytarabine infusion and just after the completion of therapy. Both required mechanical ventilation but recovered fully. Complete responses (CR) occurred in 2 of 10 evaluable patients and partial response (PR) occurred in 2 for total response rate (CR + PR) of 40%. All four responders tolerated a second course of TGAP. Both CR patients subsequently underwent matched unrelated BMT with no veno-occlusive disease or other excessive toxicity. In one CR patient, ara-CTP incorporation in the patients leukemic blasts ex vivo studied at baseline, pre chemotherapy, and repeated after 6TG and a 24-hour infusion of cytarabine showed a four-fold increase in intracellular ara-CTP, confirming our previous work in cell lines.Conclusions: TGAP is a feasible combination for patients with relapsed leukemias. A phase II study is currently under development using the maximum tolerated dose for 6TG of 100mg/m2/dose in combination with CI ara-C and IM PEG-asparaginase.

Pancreatitis during therapy of acute myeloid leukemia: Cytarabine related?

Acute pancreatitis in acute myeloid leukemia (AML) has been rarely associated with cytarabine therapy. This report attempts to characterize this toxicity. Criteria for pancreatitis was prospectively defined. Seven patients with pancreatitis were identified from an AML database and a clinical study at two tertiary care centers (n = 134). Their records were retrospectively reviewed. Seven patients with pancreatitis complicating AML therapy were identified. Median age was 36 (range 25-73) years. Median amylase was 184 (range 77-552) U/l and median lipase was 1026 (range 630-6087) U/l. The patients had received high dose bolus cytarabine (2 g/m2 i.v. bolus every 12 hours; n = 2), and continuous infusion cytarabine followed by high-dose cytarabine (100 mg/m2 i.v. CI days 1-7 then 2 g/m2 i.v. bolus every 12 hours days 8-10; n = 2), or standard dose continuous infusion cytarabine (200 mg/m2/d; n = 3) prior to developing pancreatitis. Pancreatitis occurred at a median of 10 days following day one of cytarabine administration with resolution at a median of 11 days after initial diagnosis. Six patients did not suffer major complications. One patient died of causes unrelated to pancreatitis. Five of six patients was rechallenged and all remained free of pancreatitis. One patient subsequently did develop pancreatitis on a later rechallenge. Pancreatitis in the setting of AML therapy may be an infrequent and self-limited toxicity of cytarabine. A schedule dependent toxicity with cytarabine was not identified.