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Biomedical subjects

S Giralt

Publications and source records attributed to S Giralt.

At least 73 records · Page 4Linked to original sources

Donor leukocyte infusions for multiple myeloma.

Donor leukocyte infusion (DLI) has well-documented activity in CML, but the role of DLI in other diseases is less well defined. To evaluate the strategy in multiple myeloma (MM) we evaluated 25 MM patients from 15 centers who were treated with DLI. Patients with persistent or recurrent disease after allogeneic BMT received DLI from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). Chemotherapy was given before DLI in three patients. Two of 22 patients responded completely to DLI alone and three patients responded to the combination of DLI and chemotherapy. Nine patients who had not had sufficient disease control after DLI were given additional DLIs; five of these patients had either complete (two) or partial (three) responses. Thirteen of 25 evaluable patients developed acute GVHD and 11 of 21 evaluable patients developed chronic GVHD; all responders developed GVHD. No patients developed post-DLI pancytopenia. Four patients had responses which lasted >1 year after DLI, three patients had responses which lasted <1 year, and three patients had ongoing responses but with follow-up <1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders.

Adult↗

Role of tumor necrosis factor-alpha inhibition with inflixiMAB in cancer therapy and hematopoietic stem cell transplantation.

Tumor necrosis factor (TNF)-alpha is a central cytotoxic and proinflammatory cytokine. Research on the benefits of TNF-alpha inhibition as a form of therapy has focused almost exclusively on autoimmune, inflammatory disorders. InflixiMAB, a chimeric antibody to human TNF-alpha, was recently approved for the management of Crohn disease and rheumatoid arthritis. The potential applications of inflixiMAB in the management of cancer are just beginning to be explored. This article reviews the biology, mechanism of action, pharmacology, and toxicity of inflixiMAB. Existing clinical experience and inflixiMAB's potential role as an immunosuppressant and antitumor agent in the management of cancer are also discussed.

Antibodies, Monoclonal↗

Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P =.005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P =.006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Adolescent↗

Early detection of relapse by hypermetaphase fluorescence in situ hybridization after allogeneic bone marrow transplantation for chronic myeloid leukemia.

PURPOSE: Standard G-band cytogenetic analysis (CG) provides information on approximately 25 metaphases for monitoring the presence of Philadelphia chromosome positive (Ph+) cells in chronic myelogenous leukemia (CML) patients, making the detection of a low frequency of Ph+ cells problematic. The purpose of this study was to improve the detection of a low frequency of Ph+ cells. PATIENTS AND METHODS: We combined fluorescence in situ hybridization (FISH) with long-term colcemid exposure, capturing several hundred metaphases in bone marrow cultures (hypermetaphase FISH [HMF]). Using probes that identify Ph+ cells, HMF was compared with CG analysis in the follow-up evaluations of 51 patients with CML at various time points after allogeneic bone marrow transplant (BMT). RESULTS: Thirty-five patients never showed the presence of Ph+ cells by either method. In four patients, high frequencies of Ph+ cells were detected by both methods. In the remaining 12 patients, Ph+ cells were detected by HMF at time points after BMT when they were not detected by CG. In seven of the 12 patients, low but statistically significant frequencies of Ph+ cells (0.37% to 5.20%) were detected 3 months or later after BMT, and when no intervention was initiated, all seven patients later relapsed. Based on those data, an eighth patient with mixed chimerism and a similar HMF-detected Ph+ frequency (1.8% at 27 months after BMT) was reinfused with donor lymphocytes and achieved remission with 0% Ph+ cells studied by HMF (up to 50 months after BMT). Ph+ cells detected by HMF but not by CG less than 3 months after BMT disappeared on later examination in two of four patients. After detection of Ph+ cells by HMF only, the median time to cytogenetic progression (detection of Ph+ cells by CG) was 101 days. CONCLUSION: The results demonstrate the ability of HMF to detect low but clinically relevant levels of leukemic cells not detected by CG in transplant patients. The data indicate that HMF can detect low levels of Ph+ cells before standard cytogenetics at a time that may be useful in monitoring disease status and planning clinical interventions.

Bone Marrow Transplantation↗

Low intensity regimens with allogeneic hematopoietic stem cell transplantation as treatment of hematologic neoplasia.

Conventional myeloablative conditioning regimens for allografting rely on the use of toxic myeloablative and immunosuppressive therapies to achieve engraftment and control of hematologic neoplasias. Unfortunately, these regimens have resulted in substantial morbidity and mortality. Preclinical and pilot clinical studies have shown that conditioning regimens can be reduced in intensity (resulting in reduced morbidity and mortality) since stem cell allografts can create their own space in the host's bone marrow. Initial promising results with these attenuated conditioning regimens confirm that such an approach is feasible in patients with hematologic neoplasias and genetic diseases ineligible for conventional allografting because of age and/or organ toxicity. The combination of high-dose therapy/autografting followed by a low intensity conditioning regimen (Flu-Cy protocol) and donor mobilized hematopoietic stem cell infusion (mini-allografting) may ultimately be useful in advanced resistant hematologic neoplasia. Finally, these initial promising results with attenuated conditioning regimens have been achieved in transplants with HLA-identical siblings. In the future the main goal will be to explore non-toxic conditioning regimens in the context of transplants from related MHC-mismatched or unrelated MHC-matched donors by increasing the patient's immunosuppression.

Antineoplastic Agents↗

Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation.

We evaluated demographic characteristics and graft composition as risk factors for acute graft-versus-host disease (GVHD) in 160 adult recipients of HLA-identical allogeneic blood stem cell transplants. The patients received a median nucleated cell dose of 7.9 x 10(8)/kg and median C34(+) cell dose of 5.6 x 10(6)/kg. GVHD prophylaxis consisted of cyclosporine (CSA) and steroids, tacrolimus (FK506) and steroids, or FK506 and methotrexate. Grades 2 to 4 GVHD occurred in 31% (95% CI, 23% to 39%), and grades 3 to 4 GVHD in 14% (95% CI, 8% to 20%). In univariate analyses, GVHD prophylaxis with CSA and high CD34(+) cell doses were significant risk factors for grades 2 to 4 GVHD, but diagnosis, age, use of total body irradiation, donor sex, female donor for male recipient, donor parity, donor alloimmunization, viral serology, nucleated cell dose, CD3(+) cell dose, and CD56(+) cell dose did not alter the incidence of GVHD significantly. With a CD34(+) cell dose less than 8 x 10(6) CD34(+) cells/kg, the risk of grades 2 to 4 GVHD was significantly higher for those who received CSA (39%, 95% CI, 21% to 47%) in comparison with those on FK506 (18%, 95% CI, 10% to 26%) (P =.03), but GVHD prophylaxis regimen had less impact with a higher CD34(+) cell dose (overall grades 2 to 4 GVHD rate 52%, 95% CI, 37% to 67%). GVHD prophylaxis and CD34(+) cell dose are independent risk factors for acute GVHD after allogeneic blood stem cell transplantation.

Adolescent↗

Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia.

Homoharringtonine (HHT) is a novel plant alkaloid that produced a complete hematologic remission (CHR) in 72% of patients with late chronic phase chronic myelogenous leukemia (CML). Cytogenetic (CG) remissions were noted in 31%. In this study, six courses of HHT were administered to 90 patients with early chronic phase CML (< 1 year from diagnosis). Patients then received interferon-alpha (IFN-alpha) with a target dose of 5 MU/m2 daily. Results were compared with those in a prior group of patients treated with IFN-alpha-based therapy between 1982 and 1990. Ninety-two percent of patients achieved CHR with HHT; CG responses were observed in 60% and were major in 27%. Both CHR and CG response rates were significantly higher than those seen in historical control patients after 6 months of IFN-alpha therapy. After receiving HHT, patients required lower doses of IFN-alpha to maintain a CHR. The median dose delivered was 2.4 MU/m2. This reduction in IFN-alpha dose was associated with a lower incidence of myalgia and gastrointestinal (GI) disturbances than that seen in patients treated at the 5 MU/m2 dose. Overall, CG responses were seen in 66% of the patients who received HHT and IFN-alpha compared with 61% of the historical control patients. HHT is a very effective treatment of early chronic phase CML, and ongoing trials are investigating the simultaneous administration of HHT and IFN-alpha, as well as that of HHT and low-dose cytosine arabinoside in patients failing IFN-alpha therapy.

Adult↗

Allogeneic hematopoietic transplantation as adoptive immunotherapy. Induction of graft-versus-malignancy as primary therapy.

An immune-mediated graft-versus-malignancy effect is important to prevent relapse after allogeneic bone marrow transplant for a range of hematologic malignancies and potentially some solid tumors. Graft-versus-leukemia (GVL) effects as seen in response to donor lymphocyte infusions have been most prominent against indolent malignancies including chronic myelogenous leukemia, chronic lymphocytic leukemia, and low-grade lymphoma. Acute myelogenous leukemia and multiple myeloma may also respond. An alternative strategy for allogeneic transplantation is to avoid the toxicity of high-dose chemoradiotherapy and use a relatively nontoxic, nonablative preparative regimen to achieve engraftment, allowing subsequent infusion of additional donor lymphocytes to mediate GVL. Fludarabine-based nonablative chemotherapy agents, using standard dose combinations, produce moderate myelosuppression but are sufficiently immunosuppressive to allow engraftment of an allogeneic hematopoietic transplant and generation of graft-versus-malignancy effects.

Antigens, Neoplasm↗

Allogeneic hematopoietic transplantation for mantle-cell lymphoma: molecular remissions and evidence of graft-versus-malignancy.

BACKGROUND: The presence of a graft-versus-tumor effect has been well established for various hematological malignancies but not for mantle-cell lymphoma (MCL). We report preliminary results suggestive of a graft-versus-lymphoma effect in such patients post allogeneic hematopoietic transplantation. PATIENTS AND METHODS: Sixteen patients with the diffuse type of MCL received allogeneic transplantation. Three had blastic features. Fifteen had an HLA-identical and one, a one HLA antigen mismatched sibling donor. Fifteen had stage IV disease. Eleven patients were previously treated, including one who failed prior autologous transplantation. Five patients were newly diagnosed and received transplantation after cytoreduction with three to eight courses of HYPER-CVAD (fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone) alternating with high-dose methotrexate and cytarabine. RESULTS: Eleven patients received high-dose cyclophosphamide 120 mg/kg and total body irradiation (TBI) (12 Gy given in four daily fractions). Three patients were not eligible for TBI and received the BEAM regimen. Twelve (85.7%) achieved complete and two (14.3%) partial response. Two additional patients received a nonablative preparative regimen consisting of cisplatin, cytarabine and fludarabine. One failed to engraft and later relapsed. The other patient had progressive disease one month post transplant but later achieved complete remission now durable for 14+ months after developing graft-versus-host disease (GVHD). Residual lymphoma was assessed in seven patients by polymerase chain reaction assay (PCR) for bcl-1 or immunoglobulin gene rearrangement. All had detectable disease at the time of transplant. When tested within four months post transplant, four of these patients attained molecular remission. One of the three molecular non-responders converted to a negative PCR status seven months later and one fluctuates between positive and negative PCR fourteen months post transplant. Overall survival (OS) and failure-from-progression (FFP) at three years were both 55% (95% confidence interval (95% CI): 28%-83%). For patients with chemosensitive disease, FFP and OS at one year were both 90% (95% CI: 71%-100%) compared with 44% (95% CI: 1%-88%) (P = 0.04) for those who were refractory to conventional chemotherapy at the time of transplantation. There were six deaths. These were related to GVHD (three cases), infection (one case), multiorgan failure (one case), and graft failure (one case). CONCLUSIONS: This report demonstrates the potential efficacy of allogeneic hematopoietic transplantation for MCL and provides the first evidence suggestive of graft-versus-malignancy in MCL. Data supportive of this concept include 1) achievement of remission concomitant with GVHD, 2) the conversion from a positive PCR status early after transplant to negative PCR status over time and 3) that the only relapse was in a patient who failed to engraft.

Adult↗

Graft-vs.-malignancy with allogeneic blood stem cell transplantation: a potential primary treatment modality.

The high-dose chemotherapy and radiation typically used as the preparative regimen for bone marrow transplantation produces considerable morbidity and mortality. An alternative strategy is to utilize a low-dose, non-myeloablative, preparative regimen designed not to eradicate the malignancy, but to provide sufficient immunosuppression to achieve engraftment of an allogeneic hematopoietic graft and allow subsequent development of a graft-vs.-malignancy effect. We studied this approach in patients who were ineligible for standard myeloablative preparative regimens because of advanced age or comorbidities and demonstrated that purine analog (fludarabine or 2-CDA) containing non-myeloablative chemotherapy allows engraftment of HLA-compatible hematopoietic progenitor cells, and extended remissions were observed in approximately half of chemosensitive patients with recurrent AML or CML. Patients with CLL or lymphoma have been effectively treated using a non-myeloablative regimen of fludarabine/cyclophosphamide of fludarabine, cytarabine, cisplatin. This chemotherapy is known to be non-myeloablative and mixed chimerism was anticipated. All patients with engraftment have responded and 67% have achieved complete remission. Maximal responses are slow to develop and occur gradually over a period of several months to one year. Long-term efficacy must still be determined and controlled trials are necessary comparing this approach with alternative therapies as well as standard transplantation regimens.

Child↗

Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia.

Thirty-six adults with chronic myelogenous leukemia (CML) in second or greater chronic phase, accelerated phase, or blast crisis underwent marrow or blood stem cell transplantation from an HLA-matched sibling using high-dose thiotepa, busulfan and cyclophosphamide (TBC) as the preparative regimen. All evaluable patients engrafted and had complete donor chimerism. One patient failed to clear meningeal leukemia, and one patient had one of 30 metaphases positive for the Philadelphia chromosome at 2 months post transplant. The remainder of the patients studied had eradication of CML documented by cytogenetics and/or Southern blot for BCR gene rearrangement, and 13 of 15 patients studied became negative for the BCR gene rearrangement by polymerase chain reaction. Three-year relapse rate is 42% (95% CI, 19-64%). The relapse rate was significantly lower for patients transplanted without blast crisis (9% vs 100%, P < 0.001). Eight (22%, 95% CI, 10-39%) patients had severe or fatal veno-occlusive disease (VOD). Elevated liver enzymes within 1 month prior to transplantation and transplantation using marrow were significantly associated with the occurrence of VOD. Three-year survival is 28% (95% CI, 13-43%). Survival was significantly higher for patients transplanted without blast crisis (45% vs 0%, P = 0.01). TBC is an effective preparative regimen for CML in accelerated phase but not refractory blast crisis, and it should be used with caution in patients with prior hepatopathy who have an increased risk of severe VOD.

Adult↗

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation.

Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18-56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2-4 GVHD occurred in 59% (95% CI, 38-70%), and grades 3-4 GVHD in 17% (95% CI, 1-32%). Overall survival at 1 year was 29% (95% CI, 12-45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors.

Acute Disease↗

Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients.

To assess the impact of antiviral prophylaxis during the first 3 months after transplantation on the frequency, timing, and outcome of cytomegalovirus (CMV) pneumonia during the first year, 541 adult allogeneic blood and marrow transplant recipients were evaluated. Thirty-four patients (6.3%) developed 35 episodes of CMV pneumonia at a mean of 188 days after transplantation, with an associated mortality rate of 76%. Twenty-six episodes (74%) occurred late (after day 100). Of the patients with late CMV pneumonia almost all (92%) had chronic graft vs. host disease or had received T cell-depleted transplants. Fourteen late CMV pneumonias (54%) were associated with serious concurrent infections, and 100% of these episodes were fatal. In conclusion, although the frequency of CMV pneumonia in the early posttransplantation period may be substantially reduced by prophylaxis, CMV continues to be a major cause of morbidity and mortality in the late period. Some subsets of patients need more prolonged surveillance and prophylaxis and/or preemptive therapy.

Adolescent↗

Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma.

BACKGROUND: The combination of carmustine, etoposide, cytarabine and melphalan (BEAM) is an effective autologous transplantation preparative regimen for lymphoma and has little toxicity, but the feasibility and tolerance of BEAM as a preparative regimen for allogeneic transplantation has not been established. PATIENTS AND METHODS: Thirty adults with primary refractory or recurrent intermediate- or low-grade lymphoma were treated on a prospective phase II study with carmustine 300 mg/m2 i.v. day -6, etoposide 200 mg/m2 i.v. followed by cytarabine 200 mg/m2 i.v. twice daily days -5 to -2, melphalan 140 mg/m2 i.v. day -1, and marrow or blood stem cells from an HLA-identical donor on day 0. Tacrolimus and methotrexate were used to prevent graft-vs.-host disease (GVHD). RESULTS: Median time from transplantation was 20 mos (range 6-32 months). Median maximal regimen-related toxicity grade was 2, and four patients (13%) had a grade 3-4 regimen-related toxicity. Two patients had idiopathic interstitial pneumonitis. One patient had primary graft failure, and a second had autologous reconstitution documented at three months posttransplant. Grades 2-4 acute GVHD occurred in 31%, grades 3-4 in 16%, and chronic GVHD in 54%. Day-100 survival was 70%. Twenty-three patients achieved a complete response. The two-year relapse rate was 23%, survival was 48%, and disease-free survival (DFS) was 42%. CONCLUSIONS: BEAM supports engraftment of allogeneic transplants and is a tolerable preparative regimen for allogeneic transplantation for lymphoma.

Adult↗

Reinventing bone marrow transplantation: reducing toxicity using nonmyeloablative, preparative regimens and induction of graft-versus-malignancy.

Bone marrow transplantation was initially developed as a means to deliver supralethal doses of chemotherapy and radiation for treatment of malignancies. Myelosuppression is the dose-limiting toxicity for many chemotherapy drugs and whole-body radiation. Many malignancies exhibit a steep dose-response relationship to chemotherapy or radiotherapy. Bone marrow transplantation allows escalation of doses beyond those levels which produce severe bone marrow toxicity. Doses of many agents, particularly alkylating agents and whole body radiation, can be increased three- to fivefold above their conventional maximally tolerated dose. Marrow transplantation was considered a supportive care modality to restore hematopoiesis. It has become clear, however, that the high dose therapy does not eradicate the malignancy in many patients, and that the therapeutic benefit of allogeneic marrow transplantation is largely related to an associated immune-mediated graft-versus-malignancy effect.

Antineoplastic Agents↗

Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine.

PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN-alpha) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN-alpha and ara-C induce cytogenetic responses as single-agent therapy in CML. PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN-alpha 5 megaunits/m2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN-alpha with or without intermittent ara-C (7 days/mo). RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive < 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rote was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN-alpha was 3.7 megaunits/m2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN-alpha plus ara-C combination. The incidence of CHR was higher with IFN-alpha plus daily ara-C compared with IFN-alpha plus intermittent ara-C and IFN-alpha alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN-alpha regimens (7 v 10 v 12 months; P < .01). However, with the present follow-up, the survival and time to blastic transformation were similar. CONCLUSION: The combination of IFN-alpha plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN-alpha compared with our previous studies.

Antineoplastic Combined Chemotherapy Protocols↗