Hematological Toxicity Of Chemotherapy Research Articles

Chemotherapy-Induced Oxidative Stress in Pediatric Acute Lymphoblastic Leukemia.

Introduction Plasma antioxidant capacity in children receiving chemotherapy decreases due to the effect of the disease and chemotherapy. Increased oxidative stress (OS) predisposes to an increased risk for chemotherapy-related toxicity and febrile neutropenic episodes. Materials and methods We conducted this case-control study in the hematology-oncology unit of the department of pediatrics of a tertiary hospital in Delhi, India, from November 2017 to March2019to compare OS between children with acute lymphoblastic leukemia (ALL) and healthy controls. We estimated the trends in OS as measured by the plasma total antioxidant capacity (TAC) and thiobarbituric acid reactive substance (TBARS) levels at baseline and at the completion of induction I (four weeks), induction II (eight weeks), and induction IIA-consolidation (16 weeks) phases of chemotherapy in children with ALL. We also assessed the change in OS during different phases of initial treatment and studied the association between OS and the hematological toxicity of chemotherapy (determined by the need for blood component therapy and the number of febrile neutropenic episodes) and serum cobalamin and folate levels. Results OS was significantly higher in children with ALL at diagnosis (n=23) compared to controls (n=19).The median (interquartile range (IQR)) TAC levels (mM) were significantly lower (1.21 (1.05-1.26) versus 1.28 (1.26-1.32), P=0.006), and TBARS levels (nmol/mL) were significantly higher (312.0 (216.6-398.0) versus 58.5 (46.2-67.2), P<0.001) in children with ALL at diagnosis compared to controls. OS was highest at the end of the induction I phase (four weeks) despite the patients being in clinical and hematological remission. OS at the completion of intensive chemotherapy (16 weeks) was higher than at diagnosis. A significant correlation was found between serum folate levels and TAC levels at baseline (P=0.03). Serum cobalamin levels, the need for blood component therapy, and the number of febrile neutropenic episodes did not have any association with OS. Conclusion Children withALL had significantly higher OS compared to controls, indicating that underlying disease affects the oxidative balance unfavorably. Chemotherapy itself increases oxidative stress.

Chemotherapy limiting neutropenia. Is prevention required?

Neutropenia is the most common hematologic toxicity of chemotherapy. Severe and prolonged neutropenia can cause treatment delay and dose reduction. Clinical studies indicate that reducing the relative dose intensity of regimens harms treatment outcomes, especially in breast, ovarian, and pancreatic cancers. Therefore, screening of patients at high risk of neutropenia that limits planned chemotherapy is of practical importance. Unfortunately, most clinical studies indicate only the incidence of myelotoxicity with each chemotherapy regimen, and only a few have analyzed the potential risks associated with this complication. That is significant importance in highly chemotherapy-sensitive malignancies. Such patients often receive dose intense and dose dens chemotherapy. The risk of severe neutropenia in such patients and failure to adhere to planned chemotherapy may reduce the chances of cure. Currently, there is no consensus among oncologists on the management strategy for patients with neutropenia limiting chemotherapy. This topic is a worldwide discussion. The article presents scientific evidence and clinical studies dedicated to this problem. A general analysis of clinical data and experience of oncologists will allow the medical community to develop approaches to prevent this complication.

PD-2 In vivo targeting delivery of miR-26a inhibits tumor growth and protects host from hematological toxicity of chemotherapy in breast cancer

Breast cancer is the most common malignant disease in women. In the United States, it is estimated that 252,710 women will be diagnosed with invasive breast cancer, and 40,610 women will die of breast cancer in 2017. Recent molecular-based classification categorizes the breast cancer into HER-2+, luminal-like, normal-like and basal-like breast cancer. The 12%–37% of breast cancer patients are classified into the basal-like breast cancer. The basal-like breast cancer has an unfavorable prognosis with high risk of early relapse within the first 2–5 years treatment, resulting in lower 5-year survival rate than other types of breast cancer due to lack of effective target therapy. Thus, development of novel therapeutics is urgently needed. The recent rapid expansion of genomic data greatly contributes to the understanding of disease development and progression. To translate these genetic discoveries into clinical applications, we need to develop therapeutic platforms that can specifically modulate the expression of disease-related genes in vivo. Small RNAs, such as microRNAs (miRNAs) and siRNAs function in messenger RNA silencing and post-transcriptional regulation of gene expression. Accumulating evidences have demonstrated the therapeutic potential of these small RNAs that modulate the gene expressions in many diseases including cancers. However, difficulties of in vivo delivery to specific cells have limited the potential utility of miRNA/siRNA in cancer therapy. Given the challenge of in vivo delivery, we developed a small RNAs targeting delivery platform, comprising a miRNA/siRNA sequence, a cell surface receptor-targeting DNA aptamer (a “chemical antibody”) and a complimentary passenger sequence of the miRNA/siRNA conjugated with cholesterol. These oligonucleotide sequences were heavily modified to prevent the degradation by nucleases in serum. Our newly designed delivery platform enables target-specific delivery of the small RNAs into desired cells and tissues in vivo. Our in silico gene expression analysis using data from the breast cancer and normal tissues in The Cancer Genome Atlas (TCGA) database revealed that the suppression of miR-26a expression and overexpression of a receptor tyrosine kinase, c-KIT in the basal-like breast cancer were significantly associated with disease outcome. Therefore, we hypothesized that restoration of miR-26a loss in the cancer cells using our small RNA delivery platform can inhibit the cancer growth. To test this hypothesis, we developed c-KIT targeting miR-26a delivery therapeutic using a c-KIT targeting aptamer (termed “miR-26a chimera”). This miR-26a chimera significantly inhibited the tumor growth of c-KIT+ basal-like breast cancer cells by silencing an oncogene, EZH2 in xenograft models. Interestingly, the miR-26a chimera not only enhanced the anti-tumor effect of chemotherapy (5-FU or carboplatin) in its combinational use, but also ameliorated myelosuppresive adverse effects of the chemotherapy by protecting c-Kit+ hematopoietic progenitor cells from apoptosis via silencing a pro-apoptotic gene, Bak1. By preventing the major adverse effect of chemotherapy, our new approach may allow even broader use of chemotherapeutic drugs for the advanced breast cancer. Although our study focused on breast cancer models, miR-26a as a tumor suppressor has been observed in other cancer types, including prostate cancer, pancreatic cancer and lung cancer. Likewise, the c-KIT is also widely expressed among human cancers, including gastrointestinal stromal tumors, myeloid leukemia, small-cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer and glioblastoma. Therefore, the clinical significance of our miR-26a chimera targeting c-KIT+ cancers could extend well beyond breast cancer. Besides, our targeting delivery platforms will provide not only novel therapeutics for a wide range of diseases, but also research tools to understand the roles of disease-related genes in specific tissues in vivo.

Papers of note in Science Translational Medicine 9 (387)

This week’s articles reveal a new treatment for malaria and an adjunct therapy that may reduce the hematologic toxicity of chemotherapy.

Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression.

Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first- and second-line treatment of small-cell lung cancer. Mol Cancer Ther; 15(5); 783-93. ©2016 AACR.

Abstract P3-12-04: P53 based strategy to reduce hematological toxicity of chemotherapy: A Pilot Phase II study

Abstract Background: P53 activation is a major pathway by which normal tissues respond to DNA damaging agents such as chemo and radiotherapy. We have shown that the use of very low dose arsenic (LDA) for 3 days before chemotherapy in animal models temporarily and reversibly suppresses p53 activation for about 5 days. LDA-mediated protection requires functional p53 and thus is selective to normal tissues, as essentially every cancer cell has dysfunctional p53. Arsenic Trioxide (ATO) is currently used to treat acute promyelocytic leukemia (APL) at much higher dose (50-fold higher than the dose we used for suppression of p53). The primary objectives of this trial were to: 1) define the lowest safe dose of ATO that blocks p53 activity in vitro as measured in patients(pts)’ peripheral lymphocytes and 2) assess the potential of LDA to decrease hematological toxicity in pts receiving chemotherapy. Methods: Pts with malignancies other than leukemia who were to receive at least 4 cycles of myelosuppressive chemotherapy given at least 2 weeks apart were eligible. Pts had to have no baseline p53 activation in peripheral lymphocytes but p53 had to be responsive as measured by an in vitro assay. For objective 1, dose escalation was performed at the starting dose of ATO 0.005mg/kg/day for 3 days. For objective 2, ATO 0.005mg/kg /day x 3 was given prior to chemotherapy cycles 2, 4 and 6 only. WBC, ANC, HgB and platelet counts were obtained on chemotherapy days 1 (prior to chemotherapy), 8, 15 and 22, normalized to the corresponding counts from day 1 and compared between cycles with a paired t-test. The presented analysis compares cycles 1 and 2. Results: Thirty-three evaluable pts were accrued. Chemotherapy was: TC 8, AC 7, 8 other regimens 18 pts. ATO at a dose of 0.005mg/kg/day for 3 days blocked p53 activity in vitro as measured in pts’ peripheral lymphocytes and was not associated with any toxicity. For WBC and ANC, potential protective effect was most pronounced on day 8. The mean normalized WBC counts were 0.54 in cycle 1 and 0.72 in cycle 2 on day 8 (p=0.01). 64% of pts had higher normalized WBC in cycle 2 over cycle 1, 24% remained the same (±5%) and 12% lower value. The mean normalized ANC counts were 0.53 in cycle 1 and 0.85 in cycle 2 on day 8 (p=0.02). 59% of pts had higher normalized ANC in cycle 2 over 1, 31% same, and 9% lower. There was no significant change detectable for HgB as less than 10% of pts had &amp;gt; grade 1 anemia. The mean normalized platelet counts were 0.91, 1.11 and 1.21 in cycle 1 and 0.77, 0.83 and 1.03 in cycle 2 on days 8,15 and 22 respectively (corresponding p values=0.001, &amp;lt;0.001, and 0.04). It is worth noting that &amp;gt;96% of pts had normal platelet counts or grade I thrombocytopenia. On an explorative subset analysis using the exact Wilcoxon signed rank test, the chemotherapy regimen that gained the most protective effect was AC (doxorubicin and cyclophosphamide) used for breast cancer, with mean normalized WBC counts of 0.39 and 0.46 (p=0.03) and ANC counts of 0.39 and 0.49 (p=0.02) on day 8 of cycle 1 and 2 respectively. Conclusions: Our data suggest that LDA pretreatment confers significant protection against chemotherapy induced leukopenia and neutropenia. Further study is needed to confirm its beneficial effect on AC chemotherapy. Citation Format: Carol A Jenkins, Athanassios Argiris, Ronan Swords, Anand Karnad, Martin Goros, Bradley Pollock, Zhi-Min Yuan, Chul S Ha, Richard Elledge, Kevin R Kelly, Suthakar Ganapathy, Hang Su. P53 based strategy to reduce hematological toxicity of chemotherapy: A Pilot Phase II study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-04.

Role of lipegfilgrastim in the management of chemotherapy-induced neutropenia.

Chemotherapy, irradiation, and other agents are widely used to target the process of cell division in neoplastic cells. However, while these therapies are effective against most cancers, the high proliferative rate of the cells of the hematopoietic system that produce billions of blood cells needed daily throughout life is extremely sensitive to these agents, resulting in loss of blood cell populations, which can be life threatening. Neutropenia is the most serious hematologic toxicity of chemotherapy, which can result in patient morbidity and mortality due to opportunistic infection and often is the limiting factor in dose escalation or duration of chemotherapeutic administration. Neutropenic patients often require hospitalization and incur substantial medical costs associated with anti-infective therapy. Treatment of iatrogenic and congenic neutropenia was changed in the early 1990s with the introduction of filgrastim (Neupogen®) and pegfilgrastim (Neulasta®). With the expiration of patent lives of both of these drugs, biosimilars have begun to emerge. In this review, we will summarize the chemical characteristics, pharmacokinetics, safety and efficacy of lipegfilgrastim (Lonquex®), the first long-acting biosimilar filgrastim to receive regulatory approval and enter the marketplace.

P53-based strategy to reduce hematological toxicity of chemotherapy: A pilot study

p53-based strategy to reduce hematological toxicity of chemotherapy: A pilot study

Pre-treatment lymphopenia as a prognostic biomarker in colorectal cancer patients receiving chemotherapy

Lymphopenia is a predictor of the efficacy and hematological toxicity of chemotherapy in various advanced cancers. There is little data about this relationship in colorectal cancer. In this retrospective study, the influence of pretreatment lymphopenia on hematological toxicity and the efficacy of chemotherapy was investigated in colorectal cancer patients. In total, 260 patients were included in the study. Correlations between pre-treatment lymphopenia (lymphocyte count<1,000/μl) and the occurrence of hematological toxicity and efficacy of first-line palliative chemotherapy were investigated. Lymphopenia was found in 49/260 (19%) patients. Ten of these patients with lymphopenia (20.4%) experienced severe hematological toxicity compared with 17 of the remaining 211 (8%) patients (P=0.01). Lymphopenia was identified as an independent factor for hematological toxicity. Among patients who received palliative chemotherapy, the objective response rate was significantly lower in lymphopenic patients than in the other patients (12.5% vs. 40.2%; P=0.004). Lymphopenia was strongly associated with shorter progression-free survival (median 4 vs. 7months; P=0.033) and shorter overall survival (median 16 vs. 24months, P=0.024). Multivariate analysis revealed that lymphopenia had an independent effect on survival. Our findings show that lymphopenia is an independent predictive factor for both hematological toxicity and efficacy of chemotherapy in colorectal cancer. Pre-treatment lymphocyte count may represent a simple and new predictive biomarker of chemotherapy effects in colorectal cancer patients.

Transfusion en hématologie

In the field of oncohematology, the rationale for the use of blood transfusion relies both on the proliferative advantage of the transformed clone over the others and on hematologic toxicity of chemotherapy. In France, transfusion thresholds are established by a consensus conference organized by the Agence française de sécurité sanitaire des produits de santé (Afssaps), the French health products safety agency: 80 g/l for PRC and 10 G/l for platelets concentrates in patients without additional hemorragic risk factors. For FFP especially in TTP, thresholds are more patient-related. Transfusion for sickle cell patients remains a scientific challenge.

Is There a Role for Autologous Stem-Cell Transplantation (ASCT) in Peripheral T-Cell Lymphoma (PTCL)? Final Results of a Prospective Phase II Study from the GELCAB.

The outcome of patients (pts) with PTCL receiving conventional therapy is dismal. Because of this, there is an increasing interest to investigate intensive treatments in these patients. The aim of this study was to analyze the toxicity, response and outcome of a phase II trial that includes high-dose chemotherapy (CT) plus ASCT as first-line treatment for pts with PTCL. Forty-one pts (30M/11F; median age: 47 yrs.) diagnosed with PTCL (excluding cutaneous and anaplastic ALK+), in stages II-IV and <65 years were the subject of this analysis. Twelve pts (29%) presented with primary extranodal disease, 29 (71%) were in stage IV, and 14 (35%) had bone marrow involvement. Forty-six percent of the pts had high/intermediate or high-risk IPI, whereas 49% were in the groups 3 or 4 according to the Italian Index for PTCL. Pts received intensive CT (3 courses of high-dose CHOP [cyclophosphamide 2000 mg/m2 day 1, adriamycin 90 mg/m2 day 1, vincristine 2 mg day 1, prednisone 60 mg/m2/day, days 1 to 5, mesnum 150% of cyclophosphamide dose, G-CSF 300 mg/day days 7 to 14], alternating with 3 courses of standard ESHAP). Responders (CR or PR) were submitted to ASCT. Median follow-up of surviving pts was 3.2 years (range, 0.6–8.1). Twenty-eight pts (68%) received the planned 6 courses of CT. Response rate after CT was as follows: CR, 20 cases (49%); PR, 4 (10%); failure, 17 (41%), including one pt who died because of sepsis. Hematological toxicity of CT mainly consisted of neutropenia (median nadir after high-dose CHOP and ESHAP: 0.01 and 0.4x109/L, respectively) and thrombocytopenia (23 and 29x109/L, respectively). Severe infection requiring hospitalization was observed in 38 and 15% of courses of high-dose CHOP or ESHAP, respectively. Only 17 of the 24 candidates (41% of all pts) received ASCT due to the lack of stem-cell mobilization (3 cases), severe previous toxicity (2), early relapse of the lymphoma (1) and pt decision (1). No major toxicity was observed after ASCT. The overall response after the whole treatment was: CR, 21 cases (51%), PR, 3 (7%), failure, 17 (42%). Four-year failure-free survival (FFS) was 30% (95%CI: 14–46%), whereas 4-year EFS was 51% (95%CI: 29–73%). Twenty-two pts have died during follow-up, with a 4-yr OS of 39% (95%CI: 22–56%). Notably, no significant differences in the outcome were seen among the 24 pts candidates for ASCT according to whether or not they eventually underwent this procedure. Four of 17 transplanted and 4 of 7 nontransplanted pts eventually relapsed. In addition, 2 pts died in CR after ASCT due to the development of a Burkitt-like lymphoma and lung cancer at 18 and 5 months from the procedure. Thus, 4-year EFS was 59% (95%CI: 33–85%) and 29% (95%CI 0–73%) for transplanted and nontransplanted pts, respectively (p>0.1). Four-year OS was 57% (95%CI: 31–83%) and 71% (95%CI: 37–100%), respectively (p>0.1). In summary, in this series of patients with PTCL a relatively high CR rate was obtained with high-dose CHOP/ESHAP followed by ASCT. Toxicity was manageable. The contribution of ASCT to pts outcome is debatable because of the absence of significant differences in OS and EFS of patients in CR transplanted vs. those not transplanted. Novel strategies aimed at increasing the CR rate in these patients warrant investigation.

Intra-arterial chemotherapy with docetaxel and cysplatin in combined treatment of patients with locally advanced squamouse cell head and neck cancer (SCHNC)

15528 Background: Currently the main role in chemotherapy of head and neck cancer from the 90ths is related to taxans. To elevate the effect of combination docetaxel + cysplatin and to reduce their toxic influence to the organism we have studied intra-arterial path of delivery at the combined therapy of head and neck cancer. Methods: We treated 53 patients with locally advanced SCHNC(T3, T4). All patients received 2 courses of intra-arterial chemotherapy by catheterization the feeding arteries of tumor through the external carotid artery: docetaxel-80 mg/m2, cysplatin-100 mg/m2. Further, depending on the results of chemotherapy, there were performed radiotherapy and surgical treatment in necessary volumes. Results: By analyzing the effect of docetaxel + cysplatin combination in different tumor localizations, we have concluded that the best results have been achieved in oral cavity cancer: 9 (29.1%) patients with CR and 16 (51.6%) patients with PR. Worst results have been achieved in maxilla cancer: 0 CR and 14 PR (63.6%). Hematologic toxicity of chemotherapy has manifested only in 18.8% patients (I, II grade). Non-hemathologic toxicity: alopecia 67.9%; periphery neuropathy 11.3; mucositis 5.3%. Performing radiotherapy as the second stage after chemotherapy has increased the number of patients with CR, in patients with oral cancer up to 45.1% and with maxilla cancer up to 18.1%. All results has been confirmed by cytomorphology. As of now surgical treatment has been performed for 30 patients (56.6%). 86.8% patients have been followed up for 6 to 30 months. Conclusion: This neoadjuvant intra-arterial chemotherapy with docetaxel + cysplatin allows both increasing the results of combined therapy and reducing the toxicity of chemotherapy. No significant financial relationships to disclose.

Intensive Chemotherapy (High-Dose CHOP/ESHAP Regimen) Followed by Autologous Stem-Cell Transplantation (ASCT) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL). Results of a Prospective Phase II Study from the GELCAB.

The outcome of patients (pts) with PTCL receiving conventional therapy is dismal. Because of this, there is an increasing interest to investigate intensive treatments in these pts. The aim of the study is to analyze the interim results, in terms of toxicity, response and outcome, of a phase II trial that includes high-dose chemotherapy (CT) plus ASCT as 1st-line treatment for pts with PTCL. Thirty-four pts (23M/11F; median age: 47 yrs.) diagnosed with PTCL (excluding cutaneous and anaplastic ALK+), in stages II–IV and ≤65 yrs, who have already finished planned therapy, are the subject of this analysis. Nine pts (26%) presented with primary extranodal disease, 24 (71%) were in stage IV, and 13 (38%) had bone marrow involvement. Fifty percent of the pts had high/intermediate or high-risk IPI, whereas 53% were in the groups 3 or 4 according to the Italian Index for PTCL. Pts received intensive CT (3 courses of high-dose CHOP [cyclophosphamide 2000 mg/m2 day 1, adriamycin 90 mg/m2 day 1, vincristine 2 mg day 1, prednisone 60 mg/m2/day, days 1 to 5, with mesnum and G-CSF], alternating with 3 courses of standard ESHAP). Responders (CR or PR) were submitted to ASCT. Median follow-up of surviving pts was 3.9 yrs (range, 0.5–7.6). Twenty four pts (71%) received the planned 6 courses of CT. Response rate after CT was: CR, 12 cases (35%); PR, 8 (23%); failure, 14 (42%), including one pt who died because of sepsis. Hematological toxicity of CT mainly consisted of neutropenia (grades 3–4 in 87 and 62% after high-dose CHOP and ESHAP, respectively) and thrombocytopenia (grades 3–4 in 63 and 68%, respectively). Severe infection requiring hospitalization was observed in 38 and 15% of courses of high-dose CHOP or ESHAP, respectively. Only 14 of the 20 candidates (70% of all candidates and 41% of all pts) received ASCT due to lack of stem-cell mobilization (3 cases), previous toxicity (2) and pt decision (1). No differences in the outcome were seen among these 20 pts according to whether or not they could eventually receive ASCT. No major toxicity was observed after ASCT. The overall response after the whole treatment was: CR, 14 cases (41%), PR, 5 (15%), failure, 15 (44%). Two of 14 pts in CR and the 5 pts in PR eventually progressed. Four-year failure-free survival (FFS) was 30%, whereas 4-year disease-free survival for pts achieving CR was 63%. Nineteen pts have died during follow-up, with a 4-yr overall survival (OS) of 38% (95%CI: 21–55%). Most patients died because of PTCL progression, but 2 pts died in CR due to a secondary acute lymphoblastic leukemia and to a lung cancer, respectively. IPI and Italian Index for PTCL were able to predict FFS and OS. In summary, in this series of patients with PTCL a relatively high CR rate was obtained with high-dose CHOP/ESHAP followed by ASCT. Toxicity was manageable. However, the prognosis of patients with PTCL, particularly of those not achieving CR, is still very unfavorable. [Display omitted]

Circadian-based effects of AcSDKP, with or without rhG-CSF on hematologic toxicity of chemotherapy in mice.

The hematologic toxicity of arabinosylcytosine (Ara-C) and carboplatin (CBDCA) as well as the stimulating effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on murine bone marrow vary according to their dosing time along the 24-h time scale. In the present study, we investigated whether the tolerability of Ara-C or CBDCA, given at their least toxic circadian time, could be improved further with AcSDKP, a negative regulator of hemopoiesis, rhG-CSF or both. A total of 228 B6D2F1 mice received once-daily injection of either Ara-C (42 mg/kg/d s.c.) for 7 d (d 0-6) at 8 hours after light onset - HALO) or CBDCA (40 mg/kg/d i.p.) for 5 d (d 2-6) at 16 HALO. AcSDKP (24 microg/d) was continuously infused for 7 d (d 0-6), using an osmotic minipump. rhG-CSF (400 microg/kg/d s.c.) was injected for 4 d (d 9-12) at 9 HALO. Subgroups of mice were sacrificed at 3 HALO on various days following treatment. AcSDKP significantly increased CFU-GM count on d 7 and leukocyte, neutrophil and monocyte counts on d 13 and d 16 compared to Ara-C alone. Also, rhG-CSF produced similar protective effects to those of AcSDKP with regard to leukocyte and CFU-GM counts. The combination of AcSDKP with rhG-CSF induced a further increase in total leukocytes and their subsets as compared to either agent alone, but did not alter the CFU-GM counts. Neither AcSDKP nor rhG-CSF nor their combination reduced CBD CA-induced hematological toxicity. In conclusion, AcSDKP or rhG-CSF administration further improved the tolerability of Ara-C beyond that already achieved with optimal circadian timing, while no such effect was observed in mice receiving CBDCA at the dose used. The results warrant further exploration of chronopharmacologic delivery schedules combining Ara-C with AcSDKP.