Use of recombinant human granulocyte colony-stimulating factor prior to autologous bone marrow transplantation in dogs with lymphoma

Amy E. Lane Perth Veterinary Oncology, 305 Selby St N, Osborne Park, WA 6014, Australia.

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Marisa J. Y. Chan Veterinary Medicine Specialists, 305 Selby St N, Osborne Park, WA 6014, Australia.

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Kenneth M. Wyatt Perth Veterinary Oncology, 305 Selby St N, Osborne Park, WA 6014, Australia.

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Abstract

Objective—To retrospectively assess the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) used as part of autologous bone marrow transplantation in dogs with lymphoma.

Animals—21 dogs with lymphoma at any disease stage.

Procedures—Medical records of dogs with lymphoma that underwent intensified chemotherapy and received an autologous bone marrow transplant following owner administration of recombinant human G-CSF (5 μg/kg, SC, q 12 h) for 7 days between January 2007 and July 2009 were reviewed. Results of physical examinations and CBCs performed before and at intervals during a 24-month period after G-CSF treatment were assessed. The safety of recombinant human G-CSF administration was determined via assessment of both short-term (ie, during the 7-day G-CSF treatment period) and long-term adverse effects.

Results—None of the dogs developed any adverse effect attributable to the administration of recombinant human G-CSF during G-CSF administration or during follow-up periods of 1 month to 2 years (median follow-up period, 4 months). Among the 18 dogs for which CBC results were available for analysis, mean circulating neutrophil count significantly increased after administration of recombinant human G-CSF, compared with value before treatment.

Conclusions and Clinical Relevance—Results indicated that recombinant human G-CSF administered SC at a dosage of 5 μg/kg every 12 hours for 7 days appeared to be safe and effective when used in dogs with lymphoma that were undergoing autologous bone marrow transplant.

Abstract

Objective—To retrospectively assess the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) used as part of autologous bone marrow transplantation in dogs with lymphoma.

Animals—21 dogs with lymphoma at any disease stage.

Procedures—Medical records of dogs with lymphoma that underwent intensified chemotherapy and received an autologous bone marrow transplant following owner administration of recombinant human G-CSF (5 μg/kg, SC, q 12 h) for 7 days between January 2007 and July 2009 were reviewed. Results of physical examinations and CBCs performed before and at intervals during a 24-month period after G-CSF treatment were assessed. The safety of recombinant human G-CSF administration was determined via assessment of both short-term (ie, during the 7-day G-CSF treatment period) and long-term adverse effects.

Results—None of the dogs developed any adverse effect attributable to the administration of recombinant human G-CSF during G-CSF administration or during follow-up periods of 1 month to 2 years (median follow-up period, 4 months). Among the 18 dogs for which CBC results were available for analysis, mean circulating neutrophil count significantly increased after administration of recombinant human G-CSF, compared with value before treatment.

Conclusions and Clinical Relevance—Results indicated that recombinant human G-CSF administered SC at a dosage of 5 μg/kg every 12 hours for 7 days appeared to be safe and effective when used in dogs with lymphoma that were undergoing autologous bone marrow transplant.

Colony-stimulating factors are glycoproteins that stimulate cellular proliferation, differentiation, and commitment by binding to specific receptors on the surfaces of hematopoietic cells. In vivo, G-CSF is lineage specific, exerting its effects mainly on the neutrophil lineage.1 Recombinant human G-CSF is produced in Escherichia coli by use of recombinant DNA techniques. Recombinant human G-CSF has an amino acid sequence identical to that of endogenous human G-CSF, with the exception of an N-terminal methionine necessary for expression in E coli and absence of glycosylation.1

In human medicine, autologous BMT and, more recently, stem cell transplantation have become an integral part of cancer treatment, especially for patients with hematopoietic malignancies such as lymphoma, leukemia, or myeloma.2–4 In patients who have undergone high-dose chemotherapy, recombinant human G-CSF is used to accelerate hematopoietic recovery by increasing the number of hematopoietic progenitor cells in the bone marrow and mobilizing stem cells into the peripheral circulation. Stem cell mobilization occurs via a mechanism that is not fully understood and may be via an indirect effect of the G-CSF on neutrophils and other target cells causing release of proteases that in turn effect mobilization of stem cells.4

In veterinary medicine, recombinant human G-CSF has been used in dogs in experimental5–8 and clinical settings.9–13 The use of recombinant human G-CSF appeared to be efficacious in the treatment of chemotherapy-induced myelosuppression in dogs in a study by Henry et al,9 but historical controls were used. Although no short-term adverse effects were detected, long-term follow-up of the dogs was not performed.9 Lothrop et al10 and Pratt et al11 demonstrated that administration of recombinant human G-CSF increased counts of circulating neutrophils in dogs with cyclic hematopoiesis and in clinically normal control dogs, although the numbers of treatment and control dogs included in their studies were small, making meaningful statistical interpretation difficult. In 2 other studies12,13 of young dogs with parvovirus infection, there was no significant increase in neutrophil counts in dogs treated with recombinant human G-CSF, compared with findings in the untreated control dogs, from which it was concluded that administration of recombinant human G-CSF for treatment of puppies with parvoviral enteritis was not recommended. Autologous BMT in dogs with the use of recombinant canine G-CSF has been described.14,15 To our knowledge, recombinant human G-CSF has not previously been studied in dogs undergoing autologous BMT. The purpose of the study reported here was to retrospectively assess the short- and long-term safety and efficacy (in terms of increases in neutrophil count in dogs that had received doxorubicin as part of their chemotherapy) of recombinant human G-CSF administration used as part of autologous subablative BMT in dogs with lymphoma.

Materials and Methods

Case selection—A search of the medical records at Perth Veterinary Oncology was performed to identify dogs with lymphoma that underwent intensified chemotherapy and received autologous BMT, following administration of recombinant human G-CSFa (Appendix). Dogs were eligible for inclusion in the study if a diagnosis of lymphoma, at any stage of disease, had been made on the basis of cytologic or histopathologic findings. Dogs were included in the study if recombinant human G-CSF was administered at a dosage of 5 μg/kg, SC, every 12 hours for 7 days by the owner prior to bone marrow collection and subsequent reinfusion. Dogs were not excluded if their medical records were not complete; however, patients with data missing from their record may have been excluded from certain parts of the analysis.

Medical records review—Information obtained from the medical records included signalment, previous or ongoing treatment regimens at the time of the chemotherapy and BMT, adverse effects detected during and after recombinant human G-CSF administration, neutrophil and platelet counts before and after recombinant human G-CSF administration and after administration of a high dose of cyclophosphamide (administered during the final week of the chemotherapy protocol), and duration of follow-up.

Chemotherapy protocol and recombinant human G-CSF administration—All dogs underwent chemotherapy that involved administration of vincristine, cyclophosphamide, and doxorubicin over a 12-week period (Appendix). A CBC was performed for each dog 2 weeks after the first doxorubicin treatment (week 6). At week 10, treatment with recombinant human G-CSF (5 μg/kg, SC, q 12 h) was initiated and continued for 7 days; doses of recombinant human G-CSF were administered by the dog's owner. Another CBC was performed at week 11, prior to bone marrow collection.

BMT—The method for the autologous BMT has been described previously.15 At week 10 during chemotherapy, owner-administered treatment with recombinant human G-CSF was initiated. The day after completion of the recombinant human G-CSF treatment (week 11), a lymph node aspirate specimen was collected for cytologic examination to confirm complete remission.

That same day (following confirmation of complete remission), heparin (125 U/kg, SC) was administered to each dog, and partial thromboplastin time was assessed after 2 hours. If the partial thromboplastin time was still within the reference range, another 125 U of heparin/kg was administered SC. Approximately 3 hours after the initial dose of heparin was administered, each dog was anesthetized and bone marrow (10 mL/kg) was collected from the proximal portion of a humerus. Fluids (10 mL/kg/h, IV) were administered throughout the procedure. Collection syringes were rinsed in saline (0.9% NaCl) solution containing heparin immediately prior to use. The bone marrow was collected into a harvest bag containing anticoagulant citrate dextrose solution formula-A (ratio of 1 part solution formula to 4 parts bone marrow). The collected bone marrow was examined cytologically at this time for evidence of lymphoma involvement. The volume of marrow collected was expected to provide a nucleated cell count of 5 × 107 cells/kg, but this was not confirmed microscopically. Bone marrow was strained through a coarse filter (pore size, 230 μm) into another harvest bag, then through a fine filter (pore size, 140 μm) into a transfer bag. The bone marrow was centrifuged and the RBC fraction was collected and placed into 2 cryobags, to each of which an equal volume of a 20% dimethyl sulfoxide, 40% plasma, and 40% saline solution mixture was added. The plasma used was obtained from the supernatant, which formed after centrifugation of the dog's bone marrow. The 2 cryobags were placed in a refrigerator for 1 hour, in a freezer for 2 hours, and then in a −86°C freezer for storage. Vincristine (0.7 mg/m2, IV) was administered to each dog upon recovery from anesthesia (Appendix). Seven days later (week 12), dogs received cyclophosphamide (500 to 650 mg/m2, IV) along with 6 doses of 2-mercaptoethane sulfonate sodium. The first 3 doses of 2-mercaptoethane sulfonate sodium were equivalent to 40% of the cyclophosphamide dose and were given IV at 0, 3, and 6 hours after cyclophosphamide administration; the remaining doses were equivalent to 80% of the cyclophosphamide dose and were administered orally at home by the owner at 7, 10, and 13 hours after cyclophosphamide administration. Each dog also received enrofloxacin (5 mg/kg, PO, q 24 h for 14 days) as a prophylactic measure. Two days following cyclophosphamide administration, the respective cryopreserved bone marrow sample was thawed in a 37°C water bath and administered to the dog IV. A sample of the bone marrow was submitted for bacteriologic culture and antimicrobial susceptibility testing.

Assessments—After completing the chemotherapy protocol and bone marrow reinfusion (Appendix), each dog was assessed via physical examination and a CBC weekly for the first 4 weeks. Similar assessments were then performed monthly for the following 12 months and then every 2 months for the subsequent 12 months.

The safety of recombinant human G-CSF treatment was determined by the assessment of both short- and long-term adverse effects. Short-term adverse effects were defined as any adverse clinical sign that developed during the 7-day period of G-CSF administration, as detected by the dogs' owners and a veterinarian who performed a physical examination the day after the last G-CSF dose. Specific clinical signs that owners were verbally advised to monitor for included lameness (signs of bone pain), lethargy, inappetence or anorexia, nausea, vomiting, diarrhea, dyspnea or cough, skin bruising, or rash. Long-term adverse effects were defined as neutropenia or thrombocytopenia detected during the follow-up period (commencing 2 weeks after high-dose cyclophosphamide administration [given at week 12 of the chemotherapy protocol] and autologous BMT) and persisting for > 2 weeks in a treated dog that was otherwise clinically well. The ranges used for assessing myelosuppression were derived from the Veterinary Cooperative Oncology Group common terminology criteria for adverse events16 as follows: grade 1 neutropenia, 1,500 to 3,000 cells/μL; grade 2 neutropenia, 1,000 to 1,499 cells/μL; grade 3 neutropenia, 500 to 999 cells/μL; and grade 4 neutropenia, < 500 cells/μL; grade 1 thrombocytopenia, 100,000 to 140,000 platelets/μL; grade 2 thrombocytopenia, 50,000 to 99,000 platelets/μL; grade 3 thrombocytopenia, 25,000 to 49,000 platelets/μL; and grade 4 thrombocytopenia, < 25,000 platelets/μL. If neutropenia or thrombocytopenia was detected at any time during the follow-up period, a CBC was repeated 7 days later to determine whether the abnormality was persistent. The long-term follow-up period was defined as starting 2 weeks after bone marrow reinfusion and ended if there was lymphoma relapse or death from any cause. If dogs were still alive at the time of final analysis, results were censored at this point.

To confirm the actual efficacy of increasing neutrophil counts in dogs treated with recombinant human G-CSF, CBC results were analyzed. The neutrophil count determined 2 weeks after a dog's first doxorubicin treatment (week 6; Appendix) served as an autocontrol indicator of bone marrow recovery without the addition of recombinant human G-CSF. This neutrophil count was compared with that determined 2 weeks after a dog's second doxorubicin treatment (ie, immediately upon the completion of the recombinant human G-CSF treatment [week 11]). A Wilcoxon signed rank test was used to statistically compare the 2 neutrophil counts; values of P < 0.05 were considered significant.

Results

Dogs—Twenty-one dogs were treated with recombinant human G-CSF and subsequently underwent autologous BMT between January 2007 and July 2009. The dogs' ages ranged from 4 to 12 years (median, 8 years), and weights ranged from 5.9 to 59.0 kg (median, 20.8 kg). There were 8 neutered males, 1 sexually intact male, 10 neutered females, and 2 sexually intact females. The breeds represented included Jack Russell Terrier (n = 3), Jack Russell Terrier cross (2), Border Collie (2), Border Collie cross (2), Red Heeler (2), Australian Cattle Dog cross (1), Cocker Spaniel (1), Blue Heeler cross (1), Labrador Retriever cross (1), Maltese cross (1), Miniature Schnauzer (1), Rottweiler (1), Siberian Husky cross (1), terrier cross (1), and Welsh Springer Spaniel (1).

Previous or ongoing treatments—One dog had previously completed a modified University of Wisconsin 19-week induction protocol17 for treatment of multicentric B-cell lymphoma; because of recurrence of lymphoma, the dog was eligible for inclusion in the study. Another dog had previously received carprofen and cartrophen injections to treat osteoarthritis, and 2 dogs were receiving benazepril and pimobendan to manage chronic mitral valve insufficiency.

Follow-up—Dogs were monitored by their owners for short-term adverse effects during the 7-day period of recombinant human G-CSF administration and at a physical examination performed by a veterinarian the day after the last G-CSF dose. Long-term adverse effects were assessed commencing 2 weeks after high-dose cyclophosphamide administration (given at week 12 of the chemotherapy protocol) and autologous BMT. The median period of follow-up was 4 months (range, 1 month to 2 years). All dogs were clinically well during the long-term follow-up period until censored because of lymphoma recurrence or death.

Adverse effects—Examination of the medical records revealed no adverse effects attributable to the recombinant human G-CSF during the 7-day period of recombinant human G-CSF administration as reported by the dogs' owners. No adverse effects were detected during the attending clinicians' physical examinations performed 24 hours after the last G-CSF dose was administered.

Several adverse effects were evident in the 2-week period following high-dose cyclophosphamide administration (given at week 12 of the chemotherapy protocol) and autologous BMT, including lethargy (n = 13), inappetence or anorexia (9), nausea or vomiting, (9), pyrexia (8), soft stools or diarrhea (2), and coughing (1). Three dogs were treated as outpatients with oral administration of antiemetics or antimicrobials. One dog required hospitalization for IV fluid therapy and antimicrobial treatment.

The results from the CBCs performed at 7 days after high-dose cyclophosphamide administration were available for 20 dogs. Thirteen dogs had grade 4 neutropenia, 2 dogs had grade 3 neutropenia, 1 dog had grade 1 neutropenia, and 4 dogs had neutrophil counts within the reference range. Five dogs had grade 4 thrombocytopenia, 3 dogs had grade 3 thrombocytopenia, 3 dogs had grade 2 thrombocytopenia, 4 dogs had grade 1 thrombocytopenia, and 5 dogs had platelet counts within the reference range.

The results from the CBCs performed at 14 days after high-dose cyclophosphamide administration were available for 19 dogs. One dog had grade 4 neutropenia, 7 dogs had grade 1 neutropenia, and 11 dogs had neutrophil counts within the reference range. One dog had grade 3 thrombocytopenia, 1 dog had grade 2 thrombocytopenia, 3 dogs had grade 1 thrombocytopenia, and 14 dogs had platelet counts within the reference range. For each dog, the CBC performed at 21 and 28 days after high-dose cyclophosphamide administration or at any time during the long-term follow-up period did not reveal any hematologic abnormalities.

Assessment of efficacy of recombinant human G-CSF administration—Data for 3 of the 21 dogs were excluded from this analysis because the results of the CBC performed 2 weeks after the first doxorubicin treatment (ie, performed at week 6) were not available. The median neutrophil count at 2 weeks after the first doxorubicin administration was 5.55 × 109 cells/L (range, 2.4 × 109 cells/L to 19.8 × 109 cells/L; SD, 4.1 × 109 cells/L). The median neutrophil count at 2 weeks after the second doxorubicin administration and treatment with recombinant human G-CSF (ie, assessed at week 11) was 45.87 × 109 cells/L (range, 9.5 × 109 cells/L to 77.9 × 109 cells/L; SD, 20.1 × 109 cells/L). Six of the 18 dogs included in this part of the analysis had a 10-fold increase in neutrophil count, compared with the value before G-CSF treatment. A Wilcoxon signed rank test yielded a value of P < 0.001, indicating a significant increase in neutrophil count as a result of recombinant human G-CSF treatment.

Discussion

The decision to use recombinant human G-CSF rather than a canine preparation in the present study was due to the unavailability of recombinant canine G-CSF. The human preparation causes rapid and persistent leukocytosis in dogs, largely as a result of an increase in the number of circulating neutrophils6,10,11; therefore, it was considered suitable for inclusion in the autologous BMT protocol undergone by the dogs in this study.

The dosages of recombinant human G-CSF (administered SC) used in previous studies range from 2.5 μg/kg, every 24 hours,6 to 5 μg/kg, every 12 or every 24 hours,9–11 and 20 μg/kg, every 24 hours,8 to 100 μg/kg, every 24 hours.18 The duration of treatment ranged from 3 days6 to 1 month.10 The lower dosage (administered for 3 days) only resulted in a 3-fold increase in the leukocyte count, which the authors thought was likely an insufficient increase to allow the dogs undergoing autologous BMT to recover from submyeloablative chemotherapy.6 In comparison, recombinant human G-CSF administered at 5 μg/kg, every 12 hours, for 30 days used by Lothrop et al10 resulted in a > 10-fold increase in leukocytes within approximately 2 weeks, compared with pretreatment values. In another study,18 recombinant human G-CSF was administered to 2 clinically normal dogs. One of the dogs received 10 μg/kg/d, and the other received 100 μg/kg/d for 14 days; each dosage resulted in a 10-fold increase in peripheral neutrophil count, compared with the pretreatment values. Given that a dosage > 5 μg/kg, every 12 hours, was unlikely to result in a greater increase in the circulating leukocyte count, the authors elected to administer recombinant human G-CSF at a dosage of 5 μg/kg, SC, every 12 hours for 7 days to the dogs in the present study. Only 6 of the 18 dogs included in this part of the analysis had a 10-fold increase in neutrophil count, compared with the value before G-CSF treatment. Use of the neutrophil count from the CBC performed 2 weeks after the first doxorubicin treatment as an autocontrol indicator of bone marrow recovery without administration of G-CSF was not as accurate as obtaining data from an appropriately matched control group. However, the procedure used allowed the circulating neutrophil count of each dog at 2 weeks following the first doxorubicin treatment to be compared with that individual's circulating neutrophil count at 2 weeks following the second doxorubicin treatment and administration of recombinant human G-CSF for 7 days. All other factors being equal, the difference in the circulating neutrophil count could be attributed to the recombinant human G-CSF treatment. However, each dog's bone marrow response after a second cycle of chemotherapy may be different from the response after the first cycle of chemotherapy. The bone marrow may have a comparatively slower recovery after a second cycle of chemotherapy, which would only further support the efficacy of the recombinant human G-CSF treatment. In addition, other factors could falsely increase or decrease the neutrophil count at either time point.

In human medicine, recombinant human G-CSF has been used for many years, and reports of numerous retrospective and prospective studies have described several treatment-associated adverse effects. Signs of mild to moderate bone pain, low-grade pyrexia, headaches, fatigue, nausea, insomnia, generalized itching, and splenomegaly with subsequent splenic rupture have been reported.19–24 None of the dogs in the present study had any evidence of similar adverse effects during recombinant human G-CSF administration or during the long-term follow-up period. It is possible these adverse effects were not detected because a thorough physical examination was not performed by a veterinarian daily during the week of drug administration. However, if adverse effects did develop but did not impact a dog's quality of life sufficiently to be detected by the owners, those effects could be considered mild and acceptable.

Following recombinant human G-CSF administration in humans, a decrease in platelet count to between 72% and 57% of the pretreatment value that persisted for approximately 2 weeks has been reported, although the platelet counts remained within the reference range at all times.19 Redirection of hematopoiesis to neutrophil production and the development of extramedullary hematopoiesis in the liver and spleen were speculated mechanisms of this delayed-onset thrombocytopenia.19 Fifteen dogs in the present study had thrombocytopenia (grade 1 to 4) during the first week of the follow-up period after high-dose cyclophosphamide administration; 5 dogs had thrombocytopenia (grade 1 to 3) during the second week of that follow-up period. This was most likely due to a delayed recovery of the bone marrow following a submyeloablative dose of cyclophosphamide, although it cannot be stated for certain that the G-CSF did not have a role in this. Thrombocytopenia did not result in clinical signs and resolved in all dogs with no treatment.

In the present study, dogs did develop adverse effects such as lethargy, inappetence or anorexia, pyrexia, nausea or vomiting, diarrhea, or neutropenia within 2 weeks after completing the recombinant human G-CSF treatment, which was also after submyeloablative cyclophosphamide administration and bone marrow reinfusion. These adverse effects have been reported previously following high-dose cyclophosphamide administration and BMT.15 A randomized, placebo-controlled study would be required to confirm that the adverse effects were unrelated to the administration of recombinant human G-CSF.

The most important potential long-term adverse effect associated with the use of recombinant human G-CSF in a dog is the induction of neutralizing antibodies that could subsequently cross-react with the dog's endogenous G-CSF, resulting in persistent neutropenia after marrow re-engraftment.10 This effect has been detected in dogs receiving long-term recombinant human G-CSF treatment as early as 25 days after their first dose.10 In the present study, neutropenia was not evident during the follow-up period in dogs that had received recombinant human G-CSF for 7 days. The median duration of the long-term follow-up period was 4 months (range, 1 to 24 months). Although this was a fairly short follow-up period (because of lymphoma recurrence), it is a longer follow-up period than those in previous studies and, despite the limited number of cases, suggests that the induction of neutralizing antibodies against recombinant human G-CSF is very unlikely to occur when the drug is given for only 7 days to dogs receiving chemotherapy.

Recombinant human G-CSF has been shown to induce leukocytosis, specifically neutrophilia, in dogs. In the present study, all dogs had CBCs values within reference ranges within 1 to 4 weeks after submyeloablative chemotherapy, and no dogs died as a result of neutropenic sepsis. Therefore, results of the present study have also indicated that recombinant human G-CSF can be used safely as part of subablative autologous BMTs in dogs. Assessment of a control group that did not receive recombinant human G-CSF as part of an autologous BMT would be required to confirm whether the recombinant human G-CSF was effective in significantly hastening bone marrow recovery.

The limitations of the present study are those inherent to any retrospective study, with reliance on the medical records and subjective opinions of the dogs' owners. The study had a small sample size that was further hampered by exclusion of data from 3 dogs from the efficacy analysis because results of the CBC performed 2 weeks after the first doxorubicin treatment were not available. Had the sample size been larger, adverse effects may have been detected. Concentrations of neutralizing autoantibodies or endogenous G-CSF were not assessed in any of the study dogs, the results of which could have further demonstrated the safety and efficacy of recombinant human G-CSF in this clinical setting.

It would have been beneficial to compare the results from the dogs in the present study with results from another group of dogs treated with intensified chemotherapy and autologous BMT that received recombinant canine G-CSF; however, a recombinant canine G-CSF preparation could not be accessed when the study was performed. Nevertheless, this retrospective analysis of dogs' records revealed that recombinant human G-CSF administered at 5 μg/kg, SC, every 12 hours for 7 days before administration of a submyeloablative dose of cyclophosphamide was safe in both the short and long term and was effective in increasing the peripheral granulocyte count. Use of recombinant human G-CSF appears to be suitable for use in dogs undergoing autologous BMT in situations where recombinant canine G-CSF cannot be readily obtained.

ABBREVIATIONS

BMT

Bone marrow transplantation

G-CSF

Granulocyte colony-stimulating factor

a.

Neupogen (Filgrastim), Amgen Inc, Deerfield, Ill.

References

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Appendix

Autologous BMT protocol involving high-dose cyclophosphamide administration and associated procedures used in dogs with lymphoma at any disease stage.

WeekTreatment or procedure
1Vincristine (0.7 mg/m2, IV)
2Cyclophosphamide (250 mg/m2, IV)
3Vincristine (0.7 mg/m2, IV)
4Doxorubicin (30 mg/m2, IV, if dog's weight is ≥ 10 kg; 1 mg/kg, IV, if dog's weight is < 10 kg)
6CBC
 Vincristine (0.7 mg/m2, IV)
7Cyclophosphamide (250 mg/m2, IV)
8Vincristine (0.7 mg/m2, IV)
9Doxorubicin (30 mg/m2, IV, if dog's weight is ≥ 10 kg; 1 mg/kg, IV, if dog's weight is < 10 kg)
10Recombinant human G-CSF (5 μg/kg, SC, q 12 h, for 7 d)
11CBC

Bone marrow collection

Vincristine (0.7 mg/m2, IV)
12Cyclophosphamide (500–650 mg/m2, IV)
12 + 2 daysBone marrow reinfusion

Chemotherapy treatments were each administered once at the predetermined times, unless otherwise stated.

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