Evolving Paradigms in Soft Tissue Sarcoma: Current and Emerging Targets
Emerging Cytotoxic Agents
Cytotoxic chemotherapy is still one of the mainstays of treatment for patients with STS, yet several emerging agents are being investigated in STS and are making a difference in the treatment paradigm.
Eribulin, like trabectedin, is derived from a marine compound.53 Eribulin stops cell proliferation by inhibiting the movement of microtubules, and has also demonstrated improved efficacy in liposarcoma and leiomyosarcoma when compared with other forms of STS. In a phase II study, Schöffski et al evaluated 128 patients with either adipocytic sarcoma, leiomyosarcoma, synovial sarcoma, or other sarcomas treated with eribulin 1.4 mg/m2 on days 1 and 8 every 3 weeks. The adipocytic sarcoma and leiomyosarcoma groups met the primary endpoint, and the 12-week PFS was 46.9% and 31.6%, respectively. Common grade 3 to 4 AEs included neutropenia and leucopenia.53
Eribulin was approved in January 2016 for patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-based chemotherapy regimen.54 The results were based on a phase III study by Schöffski et al in which eribulin was compared with dacarbazine.55 Among 143 patients with liposarcoma, the OS was 15.6 months with eribulin compared with 8.4 months with dacarbazine.
In 452 patients with liposarcoma and leiomyosarcoma, patients receiving eribulin had an OS of 13.5 months compared with dacarbazine (11.5 months), but the difference was not significant (HR, 0.77; P = .017).56 PFS was also not significantly different between the 2 groups. Grade ≥3 AEs were more common in the eribulin group than the dacarbazine group.
Aldoxorubicin is a prodrug of doxorubicin.57 When administered intravenously, aldoxorubicin binds to albumin, which accumulates at solid tumors due to their high metabolic rate. In the acidic environment of the tumor, aldoxorubicin becomes the active drug, doxorubicin. This mechanism of delivery reduces the risk for cardiotoxicity, which is associated with doxorubicin. In the phase IIb trial, Chawla et al randomly assigned 83 patients with unresectable STS to receive aldoxorubicin 350 mg/m2 every 3 weeks and 40 patients to receive doxorubicin 75 mg/m2 every 3 weeks.58 PFS was significantly longer with aldoxorubicin than doxorubicin (5.7 vs 2.8 months; P = .018). Common AEs included neutropenia, anemia, nausea, and mucositis. Aldoxorubicin was not associated with reduced left ventricular ejection fraction.
A new drug application is planned for aldoxorubicin as a second-line treatment for patients with relapsed STS, based on results from the phase III trial.59 Pre-NDA meetings have been arranged with the US FDA to discuss the application.
In the phase III trial, 433 patients with metastatic, locally advanced or unresectable STS who had not responded to or had progressed following a systemic regimen of non-adjuvant chemotherapy were randomized 1:1 to either aldoxorubicin or investigator’s choice of chemotherapy regimens. The manufacturer reported that in 312 STS patients, aldoxorubicin demonstrated a significantly significant difference in PFS (P = .028).59 Aldoxorubicin showed a 38% reduction in risk of progression (HR, 0.62; 95% CI, 0.44-0.88). Overall, aldoxorubicin showed an improvement over investigator’s choice of chemotherapy, but it did not reach statistical significance (HR, 0.81; 95% CI, 0.64-1.06; P = .012). AEs were similar to those noted in the phase IIb trial.
Evofosfamide, a DNA-alkylating agent also known as TH-302, is a prodrug that is activated in hypoxic environments. Because solid tumors have hypoxic regions, evofosfamide is more selective for tumor cells.60 In a phase II study, 91 patients with advanced STS received evofosfamide 300 mg/m2 on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 of each 21-day cycle.61 Chawla et al found that PFS was 6.5 months. OS was 21.5 months, and 34% of patients had a PR. The study authors concluded that outcomes compared favorably with historical outcomes.
In the phase III SARC-021 trial by Tap et al, evofosfamide plus doxorubicin was compared with doxorubicin alone in patients with locally advanced unresectable or metastatic STS.62 The authors concluded that the combination did not improve OS rates compared with doxorubicin alone (18.4 vs 19.0 months). The most common grade 3 to 5 AEs included anemia, neutropenia, and leucopenia. AEs led to death in 2.6% of patients in the combination arm and in 1% of patients in the doxorubicin alone arm.
Immunotherapy is increasingly being explored in STS, but has not yet been incorporated into standard practice.8 Many researchers and ongoing trials are currently exploring the role of immunotherapy in the treatment of STS.
Pembrolizumab is one of the PD-1 inhibitors currently being investigated in sarcomas. In the phase II SARC-028 trial, pembrolizumab was studied both in pretreated patients with soft tissue and bone sarcomas.63 Patients were treated with 200 mg of pembrolizumab every 3 weeks. Among the STS group, the ORR was 19% and the 4-month PFS rate was 44%. Common side effects included immune-related adrenal insufficiency, diarrhea, and acute interstitial nephritis.
Responses to pembrolizumab were greatest among patients with undifferentiated pleomorphic sarcoma. Among the 9 evaluable patients, the ORR was 44% including 4 patients with a PR and 3 patients with SD. As of 8 weeks, the PFS was 67%.
Among patients with leiomyosarcoma, none experienced a response, yet 6 patients had SD. The PFS rate at 8 weeks was 50%. Patients with synovial sarcoma experienced a PFS of 30%. Only 1 patient in this population experienced a PR and 2 had SD.
Nivolumab, another PD-1 inhibitor, was also tested in 20 patients with metastatic STS and 3 patients with bone sarcomas. In the trial by Paoluzzi et al, patients received 3 mg/kg of nivolumab intravenously every 2 weeks with or without additional pazopanib at 800 mg daily.64 Overall, clinical benefit was observed in 39% of the patients. Three patients experienced a PR, including 1 patient with proximal epithelioid sarcoma who also received pazopanib. Mixed responses were noted in 2 patients with STS and 4 patients with STS experienced SD. The most common side effects included grade 1 to 2 liver function transaminase elevation, especially among patients receiving the combination regimen, and grade 3 to 4 toxicities included elevated liver function transaminase levels, pneumonitis, colitis, and anemia.
An ongoing phase II trial is currently exploring combining nivolumab with or without the CTLA-4 inhibitor ipilimumab in patients with metastatic unresectable STS or bone sarcoma.65
PD-L1 expression has shown potential in other tumor types to be predictive of responses to PD-1 inhibitors, such as pembrolizumab and nivolumab. In STS, PD-1 positive lymphocytes and PD-L1 expression could be used as a prognostic indicator, and has shown a correlation with reduced OS and event-free survival rates.66 Testing patients for PD-L1 expression could be used to help select which patients would benefit more from treatment with a PD-1 inhibitor. Further, in the trial by Paoluzzi et al, the highest expression of PD-L1 was observed in those who experienced a PR.64
Current and Emerging Targets
Targets of therapy with activity in soft tissue sarcoma are depicted in FIGURE 5.67
Tyrosine Kinase Receptors
STS express factors for angiogenesis, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).68 Such factors are required for the development of sarcomas. Activation of proto-oncogenes also aid in the development of sarcomas. The inhibition of tyrosine kinase receptors disrupts cell signaling and has demonstrated clinical benefit in gastrointestinal stromal tumors (GIST) with imatinib and sunitinib and in STS with pazopanib. Although imatinib and sunitinib are effective in GIST, they have not demonstrated activity in STS as a whole.68-70 Sorafenib, an inhibitor of VEGF, is also not effective for STS.68,72
Pazopanib, a second-line therapy, is an oral multitargeted tyrosine kinase receptor inhibitor and is approved to treat patients with non-adipocytic and non-GIST STS.73 Specifically, pazopanib targets VEGF 1-3, fibroblast growth factor receptor 1 and 3, PDGF a and b, and KIT selectivity. In the phase III PALETTE trial, van der Graaf et al randomized 369 patients with advanced STS to receive pazopanib or placebo.62 Pazopanib significantly improved PFS compared with placebo (4.6 vs 1.6 months, respectively; P <.0001). No differences in OS were found, and the majority of patients had SD. Only 6% of patients had a PR. In the same group of patients, Coens et al found that pazopanib did not improve or worsen health-related quality of life.75
Using data from the PALETTE trial and a phase II trial, Kasper et al determined that 22% of patients were long-term responders and survivors with pazopanib.76 This was defined as PFS,3 of 6 months and OS,3 of 18 months. A total of 12 patients (3.5%) were treated with pazopanib for >2 years, and favorable prognostic factors included good performance status, low or intermediate tumor grading, and normal hemoglobin level at baseline.
Olaratumab, a platelet-derived PDGFR-alpha antagonist, was granted accelerated approval by the US FDA for the treatment of unresectable, advanced STS when given in combination with doxorubicin in October 2016.77 The phase II trial that led to its approval showed a 48% reduction in the risk of death over doxorubicin monotherapy (HR, 0.52; P <.05).78 OS was improved with the combination compared with doxorubicin (26.5 vs 14.7 months, respectively). PFS and ORR were also increased with the combination.
Olaratumab is administered at 15 mg/kg intravenously over 60 minutes on days 1 and 8 of a 21-day cycle, with doxorubicin also given for the first 8 cycles.79 It is recommended for patients with a histologic subtype that does not have an appropriate anthracycline-containing regimen available, and for patients whose tumors are not amenable to surgery or radiotherapy.
Anlotinib is a multitarget RTK inhibitor, and in a phase II study in China, the progression-free response at 12 weeks was 57.23% and the median PFS was 5.63 months.80 Anlotinib was particularly effective in patients with synovial sarcoma and alveolar soft part sarcoma. The most common grade 3 to 4 AEs included hypertension, pneumothorax, and thyroid hypofunction.
Regorafenib is a multikinase inhibitor, and in a phase II study, Mir et al found that regorafenib may have antitumor activity in non-adipocytic STS.81.82 In 57 patients with leiomyosarcoma and 53 patients with other STS, regorafenib significantly improved PFS compared with placebo (4.0 vs 1.9 months, P = .017; 4.6 vs 1.0 months, P= .002, respectively).81 At 6 months, rates of OS were better with regorafenib than placebo among patients with leiomyosarcoma (87% vs 75.9%, respectively; P = .013). In synovial sarcoma, regorafenib showed improved PFS over placebo (5.6 vs 1.0 months, respectively; P <.0001).82 Whereas in adipocytic STS, PFS was better with placebo compared with regorafenib (1.7 vs 1.1 months, respectively). Improvements in OS rates were not deemed clinically relevant in the trial though due to crossover.
Mammalian Target of Rapamycin
Mammalian target of rapamycin (mTOR), a kinase, participates in a pathway often deregulated in cancers.83 Ridaforolimus, temsirolimus, and sirolimus inhibit mTOR, but benefits with therapy have been limited. In a phase II study, clinical benefit response rate with ridaforolimus was 28.8% among 212 patients with advanced STS or bone sarcomas. Median OS was 40 weeks and PFS was 15.3 weeks. AEs included stomatitis, mouth ulceration, rash, and fatigue. Researchers concluded that ridaforolimus has favorable survival benefits compared with historic metrics. In a phase III trial, ridaforolimus significantly improved PFS compared with placebo (17.7 vs 14.6 weeks), but OS with ridaforolimus was similar to placebo.84 With temsirolimus, 39 out of 41 patients had disease progression and only 2 patients had a confirmed PR.85 Median time to progression was 2 months. Radiographic response to sirolimus was observed in 3 patients with perivascular epithelioid cell tumors.86
Similar to many tyrosine kinase receptor inhibitors, many monoclonal antibodies can target angiogenic factors. Bevacizumab, a recombinant human monoclonal antibody, binds VEGF. D’Adamo et al evaluated the activity of bevacizumab with doxorubicin in 17 patients with metastatic STS.87 They found that response rate (12%) with combination therapy was not higher than response rates with doxorubicin alone, but they did find that more than half of patients had SD for ≥4 cycles.
Cixutumumab, a fully human monoclonal antibody, inhibits growth factor type 1 receptor and may be active in adipocytic sarcoma.71 In a phase II study, patients with STS or Ewing family tumors received cixutumumab. At 12 weeks, the rate of PFS was greatest with adipocytic sarcoma compared with other STS. Ontuxizumab targets endosialin, which aids in the growth of tumor blood vessels.89 Endosialin is usually expressed only by tumor cells. In an ongoing phase II study, researchers are evaluating the combination of ontuxizumab with gemcitabine and docetaxel in patients with metastatic STS.
Emerging Therapies for Specific Histiologies
Lesions of leiomyosarcoma have smooth muscle features and mainly occur in the retroperitoneum.1 Some may occur in the large blood vessels. Along with liposarcoma, leiomyosarcoma is one of the most common STS subtypes, and response of leiomyosarcoma to cytotoxic therapy varies, especially in regards to tumor location. Uterine leiomyosarcoma has demonstrated response to gemcitabine with or without docetaxel.90,91 In the TAXOGEM study, Pautier et al assigned 90 patients to receive either gemcitabine alone or with docetaxel. ORRs were 19% with gemcitabine and 20% with combination therapy among patients with uterine leiomyosarcomas. For nonuterine leiomyosarcomas, ORRs were 14% and 5%, respectively. The 3-month PFS rate was 40% for uterine and non-uterine leiomyosarcomas.91 Criticisms of the study suggest that comparisons cannot be made between the study groups because the study is not appropriately powered.92 The combination of temozolomide, bevacizumab, and cabozantinib (an inhibitor of MET and VEGF) demonstrated synergistic effects among 20 patients with heavily pretreated uterine leiomyosarcoma.93
Gemcitabine with docetaxel at a fixed rate showed objective responses in 35.8% of patients with uterine leiomyosarcoma.94 CRs were noted in 4.8% and PRs in 31%. The most common grade 3 to 4 AEs included neutropenia, anemia, fatigue, and thrombocytopenia. The median PFS was 4.4 months and the median OS was more than 16 months. In a larger study of patients with uterine leiomyosarcoma, also by Hensley et al, patients taking gemcitabine and docetaxel alone experienced a median PFS of 6.2 months and a median OS of 26.9 months.95
Trabectedin improved responses in advanced uterine leiomyosarcoma over dacarbazine in a subgroup analysis of a phase III trial.96 The PFS was increased (4.0 vs 1.5 months with trabectedin and darcarbazine, respectively) but OS was not significantly improved in this pretreated population (HR, 0.89; P = .5107). Risk of progression was reduced by 43%.
Liposarcomas are adipocytic tumors.1 The most common liposarcoma is atypical lipomatous tumor/well-differentiated (ALT/WD) liposarcoma. ALT/WD liposarcoma usually occurs in the deep tissue of the extremities, especially the thigh, and is characterized by ring and giant rod chromosomes. Myxoid liposarcoma is the second most common liposarcoma and is composed of oval shaped cells. They usually occur in the extremities, and >90% of cases present with the translocation t(12;16)(q13;p11), which results in the fusion of FUSDDIT3.1
Although exact mechanisms are unclear, trabectedin promotes the differentiation of myxoid tumors by interacting with FUSDDIT3.97 This interaction may explain the response myxoid tumors have with trabectedin. Among 51 patients with myxoid liposarcoma, overall response to trabectedin was 51%, PFS rate was 88% at 6 months, and PFS was 14 months.98 Grosso et al found similar results, with a 50% response rate per RECIST and a 17-month PFS.99 As noted, trabectedin has recently been approved by the FDA for the treatment of both liposarcoma and leiomyosarcoma on the basis of phase III trial results.47
CDK4 is amplified in >90% of well-differentiated and dedifferentiated liposarcomas. The selective cyclin-dependent kinase 4/6 inhibitor palbociclib (PD0332991) was studied in a phase II study by Dickson et al.100 At 12 weeks, the PFS was 66% and the median PFS was 18 weeks. Grade 3-4 AEs included anemia, thrombocytopenia, neutropenia, and febrile neutropenia. Palbociclib has been accepted as a treatment option for patients with well-differentiated or dedifferentiated liposarcoma for retroperitoneal sarcomas.8
Eribulin has been compared with dacarbazine in 452 patients with liposarcoma and leiomyosarcoma. Patients receiving eribulin had an OS of 13.5 months compared with dacarbazine (11.5 months), but the difference was not significant (P = .017). PFS was also not significantly different between the 2 groups.80
Alveolar Soft Part Sarcomas
Alveolar soft part sarcomas (ASPS) are composed of large epithelioid cells organized in nests that are separated by thin blood vessels.1 They mainly occur in the extremities and account for <1% of all STS.1,81 Although diagnosis can occur at any age, median age of diagnosis is 30, which is younger than the age of diagnosis for STS in general. ASPS is associated with low rates of local and distant recurrence, and when metastasized, usually spreads to the lungs. It is also associated with brain metasteses.101,102 Reported 5-year OS rates range from 50% to 85%.101
Because ASPS is a rare condition, there are no standard guidelines for its management, and unlike other STS, ASPS does not respond to cytotoxic therapy.101,103,104 Targeted therapies, especially antiangiogenic therapies, may be more appropriate for ASPS treatment. ASPS expresses the translocation der(17)t(x;17)(p11;q25), which fuses ASPL-TFE3.105 This fusion increases the expression of proteins involved in angiogenesis, metastasis, and myogenic differentiation. Specifically, the fusion of ASPL-TFE3 increases the transcription and activation of MET, which promotes angiogenesis.
Sunitinib, the multitargeted tyrosine kinase inhibitor (TKI), has antiangiogenic activity. It targets VEGF2 and PDGFRB and has demonstrated activity in ASPS.106 Stacchiotti et al found that 5 of 9 patients with ASPS had PR to sunitinib 37.5 mg/day, and that median PFS with sunitinib was 17 months. They also concluded that sunitinib reduces MET activity by inhibiting RET. Cediranib targets VEGF1, VEGF2, and VEGF3 and has also demonstrated activity in ASPS.106 In a phase II study, Kummar et al evaluated cediranib 30 mg/day in 28-day cycles among 43 patients with metastatic, unresectable disease. At 24 weeks, ORR and disease control rate were 35% and 84%, respectively. In a recent phase I study, cediranib with bevacizumab, a monoclonal antibody that targets VEGF, demonstrated activity in ASPS, but dosing had to be limited for toxicity.107
Angiosarcoma is also a rare form of STS.1 Often occurring in the deep muscles of the lower extremities, angiosarcoma is recognized as an aggressive tumor, and about half of patients with metastatic disease die within 1 year of diagnsosis.1,108 Unlike ASPS, cytotoxic therapies are active in angiosarcoma.109 In a retrospective study, Fury et al determined that PFS was 4, 3.7, 4.2, and 5.4 among 125 patients receiving paclitaxel, doxorubicin, liposomal doxorubicin, or doxorubicin with ifosfamide, respectively. PFS was shorter with gemcitabine or ifosfamide alone (2.2 and 1.6 months, respectively).110 By contrast, Stacchiotti et al found that gemcitabine as a single agent was associated with a PFS of 7 months among 25 patients.111 Gemcitabine was dosed at 1000 mg/m2 every week for 3 weeks for a total of 4 doses.
Paclitaxel has also demonstrated efficacy as a single agent for the treatment of angiosarcomas.112 In the phase II ANGIOTAX study, Penel et al evaluated paclitaxel dosed at 80 mg/m2 on days 1, 8, and 15 of a 4-week cycle in 30 patients with metastatic or unresectable angiosarcoma. Median time to progression was 4 months and median OS was 8 months. Among 117 patients with metastatic angiosarcoma, weekly paclitaxel also demonstrated similar efficacy to doxorubicin. Cutaneous angiosarcomas especially received benefit from paclitaxel.113,114
Sorafenib and bevacizumab are targeted therapies that have been evaluated for the treatment of angiosarcoma. Sorafenib, a TKI, targets BRAF and VEGF receptors. In a phase II study, Ray-Coquard et al found that sorafenib only had antitumor therapy in patients pretreated with conventional chemotherapy.115 PFS with sorafenib was 1.8 months in superficial angiosarcoma and 3.8 months in visceral angiosarcoma, and OS was 12.0 months and 9.0 months, respectively. Bevacizumab maintained SD in 15 out of 32 patients and elicited a PR in 4 patients in a small phase II study.116
Dermatofibrosarcoma protuberans (DFSP) occurs in fibrous tissue and is rare, with an incidence rate of 4.2 to 4.5 cases per 1 million individuals per year.117 In DFSP, the translocation between chromosomes 17 and 22 causes the overexpression of PGDFRB. Metastatic disease occurs in about 5% of cases, and it is unclear if mitotic rate and tumor change are prognostic factors. Local recurrence occurs at higher rates, from 10% to 60%.117
As with other STS, initial treatment for DFSP is surgical resection.117 Imatinib is active in DFSP, and the US FDA has approved its use in unresectable, recurrent, and metastatic disease. In a pooled analysis of 2 phase II trials, Rutkowski et al found that 46% of patients with unresectable DFSP had PR with imatinib and a 1-year OS rate was 87.5%.118 Imatinib may also be beneficial as a neoadjuvant therapy. In a phase II study, 25 patients with primary or recurrent DFSP received imatinib for up to 2 months before surgery.119 Nine patients had clinical response and tumors decreased in size by 20%. Ugurel et al also found benefit with neoadjuvant imatinib therapy.120 In this study, tumor size decreased by 31.5% and 7.1% of patients had CR. Half of patients had PR.
Inflammatory Myofibroblastic Tumors
Inflammatory myofibroblastic tumors (IMT) is usually a pediatric cancer with a median diagnosis age of 9 years.1 Lesions are composed of myofibroblasts and inflammatory cells. They rarely metastasize (<5% of cases). The ALK rearrangement is a common genetic aberration found with IMT. Rearrangements of ALK often result in its activation and increased expression. Crizotinib inhibits ALK and MET tyrosine kinases and has demonstrated antitumor activity in case reports and a phase I study.121,122 In the phase I study, 3 of the 7 patients with IMT had PR. The other 4 patients had SD. At the time of study, 1 patient had received crizotinib for 2 years. Antiinflammatory therapies, such as corticosteroids and nonsteroidal antiinflammatory drugs, have also demonstrated antitumor activity in case reports.123-126 Ceritinib is another approved treatment for patients with IMT with an ALK rearrangement.8
Solitary Fibrous Tumors
Solitary fibrous tumors (SFT) refers to a group of benign and malignant spindle-cell tumors.127 They can be further described by their primary location — pleural, meningeal, and extrathoracic soft tissue — and do not respond well to chemotherapies, although one study supported the activity of dacarbazine.128-131 Antiangiogenic therapies may have activity in SFT. With the combination of bevacizumab and temozolomide, 11 of 14 patients had PR per Choi, and PFS was 9.7 months.130 With sunitinib, a multitargeted TKI, PFS per RECIST was 6 months among 35 patients.111
Synovial sarcoma varies in epithelial differentiation and despite the name, is not associated with the synovium, although it often occurs near the joints.1 It is associated with the translocation t(x;18) (p11;q11), which can result in the fusion of SYT-SXX. Synovial sarcoma responds well to ifosfamide. In a 1993 study, better response was observed with ifosfamide plus doxorubicin when compared with other doxorubicin combinations.132 When ifosfamide was evaluated as a single agent, 33% of patients receiving high-dose ifosfamide had partial response, and OS was 12 months.133 Although ifosfamide may have activity as a single agent, Spurrell et al found that response rate with the combination of doxorubicin and ifosfamide was higher than either agent alone.134
In preclinical studies, trabectedin has also shown promise in treating patients with synovial sarcoma, which could be translated into in-human clinical trials in the future.135
Adoptive cellular therapy with autologous lymphocytes genetically modified to express an NY-ESO-1–specific T-cell receptor and dendritic cell vaccination has shown promise in synovial sarcoma, as NY-ESO-1 is expressed in approximately 70% of synovial sarcomas. The T-cell therapy received a US FDA breakthrough therapy designation for patients with inoperable or metastatic pretreated synovial sarcoma who harbor HLA-A*201, HLA-A*205, or HLA-A*206 alleles and whose tumors express the NY-ESO-1 tumor antigen.136
The designation was based on a phase I/II trial where the therapy showed a response rate of 50% in patients with unresectable, metastatic, or recurrent synovial sarcoma treated with prior chemotherapy. Forty-two percent of patients who received any dose survived more than 1 year.
In an open label, non-randomized, multi-cohort study of NY-ESO-1 in patients with synovial sarcoma, patients with high expression of NY-ESO showed promising efficacy.137 The ORR was 50% among patients with high NY-ESO-1 expression and fludarabine and cyclophosphamide with 1 patient experiencing a CR and 5 experiencing a PR. The median duration of response was 31.5 weeks, for a maximum of 47.3 weeks. The most common treatment-emergent AEs were leukopenia, lymphopenia, neutropenia, anemia, nausea, and thrombocytopenia.