WO2007042851A1 - Optimizing malignant disease-free survival by combined modality treatment - Google Patents
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Abstract
This invention relates to systems and methods for development and implementation of treatment plans named integrated diagnosis treatment combinations with the aim to improve cure at diagnosis of malignant diseases, among which breast cancer, by combinations of cytotoxic cytoreductive compounds, supportive measurements and allogeneic cell transplantation. Once such method is comprised of collecting information, developing a treatment optimization model and implementing the model on a global basis through output methods and systems. The invention furthermore provides a model for studying treatment plans and compounds for prevention and treatment of side effects.
Description
OPTIMIZING MALIGNANT DISEASE-FREE SURVIVAL BY COMBINED MODALITY TREATMENT
FIELD OF THE INVENTION
This invention relates to systems and methods for development of treatment plans for curing malignant diseases among which breast cancer at diagnosis of the disease condition, not curable by surgery only and responsive to chemotherapy and allogeneic immune response. This invention relates to combined modality treatment comprised of intensive remission- induction therapy, an autologous transplant strategy and a non-myeloablative reduced intensity conditioning allogeneic transplant to obtain optimal cytoreduction by cytotoxic compounds and eradication of residual tumor cells by an allogeneic immune response and therewith cure during the first sequence of such therapy for the malignant diseases. This invention relates to a method for optimization and implementation of such treatment plans.
BACKGROUND OF THE INVENTION
Ablative allogeneic transplants have been administered since the 1970's for leukemia and are in combination with induction/consolidation chemotherapy at diagnosis of leukemia the most powerful treatment to induce disease free and overall survival. The results were significantly better than achievable by induction/consolidation chemotherapy and autologous transplants. The combination therapy added powerful immunotherapy to cytotoxic cytoreductive treatment. Ablative allogeneic transplants were though associated with high risk of treatment related mortality, but disease recurrence was 2 to 3 times less than seen after high-dose autologous transplantation in same setting and disease free and overall survival was in general better compared to high-dose autologous transplants. Moreover disease free and overall survival was significantly better when the ablative allogeneic transplant was given in first complete remission. In the late 90s investigators started to realize that ablation was not required for donor hematopoietic reconstitution; conditioning regimens became not ablative (non-myeloablative or reduced intensity conditioning).
Non-myeloablative transplants appeared associated with less treatment related toxicity than ablative transplants which offered to broaden the indications. Responses were observed in other hematologic malignancies and in a few solid tumors among which breast cancer. It was likely that non-myeloablative transplants would open a door for improvement of cure of hematologic malignancies and solid tumors. The current invention is based on these early observations.
SUMMARY OF THE INVENTION
The following system to develop and implement the treatment plan.
Objective description, retrospective research, disease definition, eligibility description, model planning, design, protocol development, implementation, management, evaluation of results, refinement of the treatment plan for implementation as integrated diagnosis treatment combination through output methods and systems.
The treatment of non-resectable malignant disease consists of a combination of treatment modalities to be planned at diagnosis. In general the disease is at that moment under planned as result of disciplines not familiar with intensive treatment; considerable undertreatment with as result death is the cause. For tumors responsive to an allogeneic immune response, addition of allogeneic transplantation when the disease is in documented first complete remission is critical
to enhance durable complete responses. Allogeneic immune competent cells eradicate residual malignant cells present below the detection level. Without allogeneic transplantation these cells will induce disease recurrence.
Hematologic malignancies and breast cancer are examples of malignant diseases responsive to an allogenic immune response. For leukemia this was known since years and although all components are present to cure >80% of patients survival in first complete remission due to failure to treat appropriately less then 50% survive. Even with the agents available to cure the right treatment is not given. Herein all aspects to improve are addressed.
The general principle of the treatment plan is to achieve fast disease control and complete remission, consolidate the complete remission with least risk of treatment related mortality and administer a the non-myeloablative reduced intensity conditioning. In all these therapies the cytotoxic cytoreductive compounds are used in combination at the not-ablative dose level.
To accomplish the goal one model recommends intensified induction-remission chemotherapy plus stem cell collection and/or an autologous transplant strategy prior and a non-myeloablative reduced intensity conditioning allogeneic transplant. Factually it are combination of cytotoxic cytoreductive compounds, intensified, semi-high dose or non-myeloablative reduced intensity as compared to standard, high-dose and ablative. Monoclonal antibodies may be part of the combinations of cytoreductive cytotoxic compounds. These components together with supportive compounds for treatment or prophylaxis of side effects and if required radiotherapy on former disease burden are described in the treatment plan.
Intensification of induction therapy is achieved by reduction of the interval between cycles (dose density) and/or intensification of combination therapy per cycle. Intensification has been shown to enhance complete response rates and reduce development of tumor cell resistance. Granulocyte colony stimulating factor is added to make dose intensification and dose density feasible and to mobilize progenitor cells from the bone marrow.
High-dose combinations of cytotoxic cytoreductive are associated with treatment related mortality regardless of autologous stem cell support; use of semi-high-dose intensity combinations of cytoreductive, cytotoxic compounds at an interval of weeks to eliminate treatment related mortality. Moreover, semi-high-dose combinations of cytoreductive, cytotoxic compounds at an interval enhance the complete response rate of intensified induction therapy. Semi-high-dose is defined as half the dose of reported regimens. Semi-high dose has not been reported in this context.
Two semi-high dose combinations of cytoreductive, cytotoxic compounds with autologous stem cell support at an interval followed by non-myeloablative reduced intensity combinations of cytoreductive, cytotoxic compounds prior to allogeneic stem cell infusion reduces overall treatment related mortality compared to conventional ablative cytoreductive, cytotoxic conditioning combinations of compounds in allogeneic transplantation. Moreover, semi-high-dose conditioning combinations of cytoreductive cytotoxic compounds
make subsequent non-myeloablative reduced intensity conditioning better feasible than high- dose combinations of cytoreductive cytotoxic compounds. Non-myeloablative reduced intensity conditioning is required to assure rapid three lineage engraftment.
Two semi-high dose combinations of cytoreductive cytotoxic compounds prior to autologous stem cell infusion and non-myeloablative reduced intensity combinations of cytoreductive cytotoxic compounds in allogeneic transplantation at a fixed minimal interval replaces conventional ablative conditioning in allogeneic transplantation. Autologous stem cell infusion is a supportive method.
The non-myeloablative reduced intensity conditioning transplant consists of combinations of cytoreductive, cytotoxic compounds; immune modulatory drugs and acute graft versus host disease prophylaxis is included. Moreover a combination of at least two compounds is required to control acute graft versus host disease well. To prevent chronic graft versus host disease T- cell suppression and B-cell depletion can be used.
The intervals between combinations of compounds regardless in which treatment component are defined in order to provide a basis for computation of dose delay, and therewith compromisation of overall dose intensity. Combinations of compounds are defined per disease. Compounds may be chemotherapeutica, monoclonal antibodies or immune modulatory compounds.
Complete remission is defined by clinical, radiological, morphological, immunophenotypic, cytogenetic or molecular remission.
Allogeneic immune competent cells are CD8+ cells and a curative element there where combinations of cytotoxic cytoreductive compounds cannot induce cure; The dose level of CD8+ cells is at the lOVkg dose level. The allogeneic immune response eradicates residual tumor under the detection level. Any cell sources can be used (bone marrow, peripheral blood or cord blood).
Supportive compounds and methods are critical to make this treatment feasible. They are an integral part of the treatment plan. The CD34+ cells dose to be infused for support after semi- high-dosing of compounds is at the 106/kg dose level, in general >lxlO6/kg.
The compounds and methods to deliver the treatment and supportive measurements are called treatment plans or integrated diagnosis treatment combinations; it is upfront defined which treatment is to be given and the budget for the overall treatment is defined in such integrated DTC. The significance of integrated diagnosis treatment combination is that if treatment related mortality of the overall therapy can be reduced to 0-15%, hypothetically 70-100% of patient can be cured with appropriate treatment at diagnosis. The goal is to use effective and least expensive methods to achieve the goal.
The methods are described in a manual; the manual may be a protocol; manuals are commercialized for world wide implementation. Protocols serve to support studies and describe
the type of drug combinations, dose and dosing and most important timing and mechanisms for delay of treatment. The treatment plans are named integrated diagnosis treatment combinations and are presented to the insurance industry as cost efficient treatment options to cure cancer instead of palliation.
In breast cancer as example for solid tumors the treatment plan typically consist of four cycles of dose dense combinations of intensive cytotoxic cytoreductive compounds as induction treatment, + two cycles of semi-high-dose or reduced intensity cytotoxic cytoreductive compounds with as supportive action autologous stem cell rescue and a non-myeloablative reduced intensity combinations of cytotoxic cytoreductive compounds (conditioning) prior to allogeneic stem cell source infusion. Supportive measurements are included.
In solid tumors surgery anticipates the treatment or is integrated in the schedule.
In acute leukemia the treatment plan typically consists of two to four cycles of dose dense combinations of intensive cytotoxic cytoreductive compounds as induction treatment, two cycles of combinations of cytotoxic cytoreductive compounds, one to consolidate and one to replace high dose autologous stem cell infusion and non-myeloablative reduced intensity combinations of cytotoxic cytoreductive compounds (conditioning) prior to allogeneic stem cell infusion. Supportive measurements are included.
In myeloma the same strategy will be followed as in breast cancer, whereby the induction therapy newly consists of cycles of dose dense combinations of intensive cytotoxic cytoreductive compounds atypical for the disease but typical for lymphoma.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 Overview of used non-myeloablative reduced intensity conditioning regimens.
Figure 2 Integrated diagnosis treatment combination algorithm
DEFINITIONS
Standard dosing: is the standard dose described in the literature for single and combinations of compounds
Intensive dosing: is a dose that is higher than the standard dose for at least one of the single compounds or for the combination of compounds than the standard in the literature. Semi-high-dose dosing: is half the dose (50%) of high-dose in the literature for single compounds and combinations; it related here to compounds used in high-dose autologous stem cell infusion
Non-myeloablative reduced-intensity dosing = not-ablative dosing: initially the term non- myeloablative was used for not ablative; later reduced intensity was introduced for not ablative. The terms are now mixed up whereby non-myeloablative is attached to the regimens at the left end of figure 1 and the reduced intensity is used for regimens toward the right in figure 1.
Semi-high and reduced-intensity could be used in either setting, autologous or allogeneic. One of our other models uses reduced intensity; by which reduced intensity is not exact 50% of reported doses.
Cytoreductive cytotoxic compounds: any compounds that are cytotoxic for tumor cells and reduce the tumor cell burden such as chemotherapeutica and monoclonal antibodies
DETAILED DESCRIPTION OF THE INVENTION
Background and rationale
Ablative allogeneic transplantation induced best long-term outcome when administered in first complete remission. The therapeutic effect of these transplants is defined by cytotoxic cytoreductive combinations of compounds and immune competent cells in the graft. Disease free and over all survival are significantly better and side effects of treatment are less in patients transplanted in first complete remission compared to second complete remission.
Champlin et al. Blood 2000;95:3702-3709; Saikia et al. J Assoc Physicians 1999; 47(8): 770- 773; List et al. Bone Marrow transplant 2000;35(3):283-291; Bacigalupo A et al. Exp Hematol 1998;26(5):409-414. 1-4). Bacigalupo et al. Haematological 2004;89: 1238-1247.
Treatment-related mortality after ablative allogeneic transplants did restrict use of this treatment modality to aggressive hematologic malignancies. The high treatment-related mortality of ablative allogeneic transplants and growing awareness that ablation was not required for engraftment led more and more to use of non-myeloablative reduced intensity conditioning transplants around the turn of the century.
In non-myeloablative reduced intensity conditioning the dose of the cytoreductive cytotoxic compounds is reduced compared to ablative conditioning. The degree of myeloablation of the conditioning regimen defines the probability of engraftment. In Figure 1 the degree of ablation of various conditioning regimens is shown. The regimens at the lower end of conditioning are associated with risk of engraftment failure. Engraftment failure compromises the function of the graft and is associated with higher relapse rate. Adequate dosing is important for trilineage engraftment.
Hochhaus A et al. Leukemia 2000; 14:998-1005; Slavin et al. Blood 1998;91:756-763; Gomez-
Almaquer et al. Bone Marrow transplant 2000;25: 131-133; Escalon et al. J Clin oncol
2004;22:2419-2423.
Baron F, et al Biol Blood Marrow transplant 2005; 11:272-279; Kerbauy FR et al. Leukemia
2005; 19:990-997; Sloand E, et al. Bone marrow transplant 2003;32:897-901.
The curative effect of allografts is exerted by immune competent cells inducing a graft versus malignancy effect. This graft versus malignancy effect is exerted by CD8+ T-cells, as is graft versus host disease. CD8+ cell inactivation by monoclonal antibodies leads to loss of the graft versus leukemia effect. The graft versus host disease effect is exerted primarily by CD4+ cells and to a lesser extend by CD8+ cells. CD4+ cells blocking does not affect the graft versus host
disease efficiently of CD8+ cells. By induction of a graft versus malignancy effect CD8+ cells eliminate residual tumor cells; CD8+ cells exert therewith a most powerful therapeutic effect. The effect is seen haematological malignancies and solid tumors. The CD8+ cells therewith eradicate residual malignant cells, that are no longer detectable when the patient is in complete remission prior to the non-myeloablative transplant.
Stelljes et al. Blood 2004;104:1210-1216; Weiss et al. Cytokines Cell MoI Ther 1999;5:153-158; de La Reselle et al. Bone Marrow Transplant 1999;23:951958; Transplantation 2003;76:297- 305; Sykes et al. J Immunol 1993;150:197-205; Michalek et al. PNAS 2003;100:l 180-1184;
Graft versus host disease is a side effect of allogeneic transplantation and the major cause of treatment related mortality. In non-myeloablative transplantation acute graft versus host disease can in general be well managed with prophylactic compounds. Therewith chronic graft versus host disease has become of more concern; is has become a major cause of death. Chronic graft versus host disease (GVHD) is a long term side effect of allogeneic transplants that is age dependent and occurs on average in 0-10% of pediatric and 50% of adult non-myeloablative allogeneic transplants, despite treatment with immune suppression.
Djulbegovic et al. Cancer Control 2003; 10: 17-41; Prakash et al Biol Blood & marrow Transplant 2005; 11:403-422; Satwani P, et al. Biol of Blood and Marrow Transplantation 2005; 11:403-422. Goldman JM, et al. Ann Intern med 1988; 108:806-814; Sehn LH, et al. J Clin Oncol 1999;17:561-568; Van HoefME.Blood 2002;15:1508-1509; Crawley C, et al. Blood 2005;105:4532-4539; Lee SJ. Blood 2005; 105:4200-4206.
Promissing results have been reported from treatment with the humanized CD20 monoclonal antibody by treatment with rituximab. Complete response of chronic graft versus host disease phenomina have been reported even in patients with rapidly progressive disease. Complete response has also been reported in steroid refractory single manifestations of the disease.
Non-myeloablative reduced intensity conditioning transplants in first complete remission hold promise for transfecting the genes that induce cure of cancer in first complete remission.
Combined modality treatment
In treatment of malignant diseases a relationship exists between chemotherapy dose-intensity and tumor response. The highest probability of complete remission is during the first treatment when intensive cytotoxic cytoreductive combinations of compounds are administered. Dose dense and/or intensified chemotherapy induces higher response rates than standard treatment. Moreover, the reduce development of chemotherapy resistance development. High-dose combinations of cytotoxic cytoreductive compounds in autologous transplants add dose intensity and increase the complete response rate. However five years survival is in general not significantly increased due to relapse. The role of high-dose autologous transplantation is to enhance the complete response rate achieved by intensive induction and prepare to let the non- myeloablative reduced intensity conditioning transplant exert an optimal effect.
Hortobagy et al. J Clin Oncol 1987;5:354-364. Ferguson et al. Br J Cancer 1993;67:825-829.Van Hoef et al. Ann Oncol 1994;5:217-224. Brufman et al.Ann Oncol 1997;8:l55-62. Pfreundshuh et al. Blood 2004; 104:626-633. Segeren et al Br J Haematol 1999;105:127-30; Egerer et al. Support Care cancer 2001;9:380-385.
High-dose combinations of cytotoxic cytoreductive compounds are though associated with treatment related mortality; the incidence may depend on the type of conditioning regimen and disease; treatment related mortality in breast cancer varies from 0 to 3 %; in leukemia the incidence may be higher.
Antman et al. J Clin Oncol 1997; 15: 1870-1879; Pedrazzoli, Bone Marrow Transplant 2003;32:489-494. Laudi et al. Biol Blood Marrow transplant 2005;l 1:129-35. Levine et al. Blood 203;101:2476-2462; Nivison-Smith et al Intern Med 2005;35:18-27. Garderet et al. Blood 2005;105:405-409.
To eliminate treatment related mortality seen after high dose combinations of cytoreductive cytotoxic compounds in autologous transplantation by two semi-high-dose combinations of cytoreductive cytotoxic compounds at an interval. Some loss of dose intensity is made up for by the subsequent non-myeloablative reduced intensity conditioning. Moreover semi-high-dose conditioning makes the sequence of therapeutic options named herein feasible.
Semi-high-dose combinations may remain high-dose combinations of cytotoxic cytoreductive treatment prior to autologous transplantation. Moreover in this model the number of semi-high- dose combinations is restricted to two; other models are considerable whereby the number of semi-high-dose cycles increases to the cost of induction treatment.
In this model the standard is defined per treatment plan and consists of two to four dose dense combinations of cytotoxic cytoreductive compounds at an interval and/or two semi-high-dose combinations of cytotoxic cytoreductive compounds with autologous stem cell support or an equivalent at an interval and/or a non-myeloablative reduced intensity conditioning transplant in certain hematological malignancies and solid tumors.
In acute leukemia the autologous transplant strategy may be replaced by a high-dose cycle cytarabine.
Dose intensity is defined by dose per cycles, number of cycles and interval between cycles. Granulocyte colony stimulating factor makes dose density feasible and meanwhile supports mobilization of hematopoietic cells from the bone marrow; such cells are collected for infusion after semi-high-dose autologous transplants and as back up if considered necessary.
The overall treatment is defined including doses and intervals between doses and components of the overall treatment plan. A clause defines dose delays. Figure 2 describes therapeutic elements of a diagnosis treatment combination but leaves out the supportive measurements. Figure 3 describes a typical diagnosis treatment combinations for the various diseases for breast cancer.
Supportive compounds are among others granulocyte colony stimulating factor, anti-infective prophylaxis, anti-emetic prophylaxis and immune suppressive as graft versus host disease prophylaxis or as treatment and are proposed in the treatment plan. Hematopoietic cell infusion form autologous and allogeneic source are also supportive measurements for hematopoietic recovery.
Indications for non-myeloablative reduced intensity conditioning are leukemia, lymphoma, myeloma, neuroblastoma, breast cancer and solid tumors.
Weiden et al. N Engl J Med 1979; 19: 1068-1073; Champlin et al. Blood 95:3702-3709; Weisdorf et al. Blood 1997;90:2962-2968; Gratwohl et al. Bone Marrow Transplant 2003;32:102-106; Eibl et al. Blood 1996;88: 1501-1508; Ueno et al. J Clin Oncol 1998; 16:986-993
Non-myeloablative reduced intensity conditioning transplants have been reported to substantially reduced costs of treatment, a reason to define integrated diagnosis treatment combinations.
Leong et al. Med J malaysia 2003;58:229-235; Ruiz-Arguelles. Int J hematol 2002;76 suppl 1:376-9;
Results of non-myeloablative reduced intensity conditioning transplants in chronic myeloid leukemia in first chronic phase are promising, in particular in countries where applications early during the disease course is important to save costs of treatment.
Or et al. Blood 2003;101:414-445; Massenkeil et al. Hematol J 2004;5:395-402; Martino et al. Haematologica 2003;88:555-560; Hamaki et al. Bone Marrow Transplantation 2005;35:549-546.
Various non-myeloablative reduced intensity conditioning regimens have been applied. Non myeloablative conditioning by 2 Go or fludarabine and cyclophosphamide alone have been reported to be associated with graft failure and seems to compromise disease outcome. Rapid trilineage engraftment is seen in non-myeloablative reduced intensity conditioning transplants.
Or et al. Blood 2003;101:414-445; Baron et al. Biol Blood Marrow transplant 2005; 11:272-279; Kerbauy et al. Leukemia 2005; 19:990-997; Sloand et al. Bone marrow transplant 2003;32:897- 901; Carella et al. Lancet 2005;366:318-320.
Allogeneic transplantation for lymphoma became feasible with venue of non-myeloablative transplants. It is currently only applied in advanced disease. However, results are more promising. Even in advanced disease durable complete remissions are reported. It is warranted to bring cure upfront which is feasible with the strategy herein proposed.
Anderlini et al.Bone Marrow transplant 2005;35:943-951; Mitterbauer et al. Br J haematol 2002;18:132-135; Escalon et al, J Clin Oncol 2004;22:2419-23; Corradini et al J Clin Oncol 2004;22:2172-6.
In multiple myeloma several authors have reported use of non-myeloablative reduced intensity conditioning in advanced disease. It will be critical to administer intensive dose dense induction and semi-high-dose conditioning and combined transplants to stage I patients to induce cure. The strategy proposed herein aims to focus on stage I patients, stage II and III are permitted; the goal will be to achieve CR prior to allogeneic transplantation
Maloney et al. Blood 2003;102:344-3453; Kroger, et al. Blood 2002;100:755-769; Kroger et al 2002; 100:3919-3924.
In advanced metastatic breast cancer non-myeloablative reduced intensity conditioning transplants have been applied in advanced disease only to confirm the immune response seen in solid tumors.
Bishop et al.J Clin Oncol 2004;22:3886-3892; Ueno et al. Blood 2003;102:3829-3836. Bregni M et al. Blood 2002;99:4234-4236; Carella et al. Lancet 318-320.
Survival in metastatic breast cancer treated with standard first line treatment is 10%. High dose autologous transplants significantly enhance complete response rates and disease free survival at five years follow-up but not overall survival. This indicates treatment related mortality of high- dose autologous transplants.
In high-risk lymphnode positive 5 years survival is in general 60%, where as it is 50% in high- risk lymph node positive breast cancer; high-dose autologous transplants add disease free survival advantage in high risk breast cancer of about 10%. The treatment plan offers a probability of >85% disease free and overall survival.
Farquhar et al. The Cochrane Database of Systematic review 2005, Issue 3 Art. No
CD003142.pub2.
Rodenhuis et al. N Engl J Med 2003;349:7-16.
Donor typing is performed at diagnosis; patients with a donor receive a non-myeloablative transplant; patients without donor have received optimal treatment. Therewith this treatment plan provides a natural control group even in phase I-II, given the fact that a donor cannot be found for all patients; HLA-identical sibs provide a donor in 25% or patients and a matched unrelated donor can be found for 50-60% of patient with current methods. However, only about 50% of patients for whom an unrelated donor was found received a transplants. Thus in Caucasians well- matching donors can be found for about 70% of patients and about 50% was transplanted.
Complete remission can be assessed clinically, morphologically, cytogenetically or molecular. Methods are immunohistochemistry, flowcytometry, immunophenotyping, genotyping, fluorescent in situ hybridization and polymerase chain reaction and other methods.
Radiotherapy if applied is on former lesions of bulk disease.
Cytotoxic cytoreductive compounds in intensive induction in acute myeloid leukemia at this
moment among others daunorubicin, idarubicin, amsacrine, cytarabine, mitoxantrone, etoposide, methotrexate; monoclonal antibodies may be included. Intervals between cycle are standard four weeks. Dose density can be achieved by three week intervals.
Semi-high dose autologous transplants cycles are generally high dose cycles and cyrarabine containing.
The general non-myeloablative reduced intensity conditioning regimens induce fast three lineage engraftment. The interval between components of treatment is four weeks unless toxicity dictates different.
Interval between the start of last cycle and the first date of the allogeneic transplants eight weeks of more if dictated by toxicity.
Cytotoxic cytoreductive compounds in intensive induction in acute lymphoblastic leukemia include among others daunorubicin, vincristine, asparaginase, steroids, amsacrine, mitoxantrone, etoposide, cytarabine, methotrexate; imatinib is a highly active compound and reduced the toxicity of former regimens. Intervals between cycle are standard four weeks. Dose density can be achieved by three week intervals. Semi-high-dose cycles were high-dose cycles but in view of promising results of imatinib offer new opportunities. Novel induction methods followed by two semi-high doses of cytarabine 8 g/m2 in two days and imatinib 800 mg/d for seven days respectively.
The general non-myeloablative reduced intensity conditioning regimens induce fast three lineage engraftment. The interval between components of treatment is four weeks unless toxicity dictates different; same applies to the additional high-dose cytarabine course.
Interval between the start of last cycle and the first date of the allogeneic transplants eight weeks or more if dictated by toxicity.
Skin et al.Bone Marrow Transplant 2005; J Ploenza et al; Haematological 2005;90(9):1275- 1277; Leuk 2005;12(9):1509-1516.
Cytotoxic cytoreductive compounds in intensive induction in lymphoma are given as published regimen, adriamycin, epirubicin, bleomycine, vinblastine, dacarbazine, cyclophosphamide, vincristine, prednison and rituximab are included in regimens. Typical currrent induction regimens are ABVD and CHOP. Intervals between cycles are standard four weeks. Dose density can be achieved by reducing the interval to two or three weeks. Replacement of adriamycin by epirubicin and intensification of the dose is recommended.
Semi-high-dose combination of cytotoxic cytoreductive compounds consist of half the reported doses for the well known regimens BCNU, etoposide, arabinoside, cyclophosphamide or melphalan. Cycles with autologous stem cell rescue are given at 4 weeks interval. The general non-myeloablative reduced intensity conditioning regimen induces fast three lineage engraftment. The interval between the components of treatment is set (intensive induction and first semi-high-dose and last semi-high-dose and non-myeloablative reduced intensity combinations of cytotoxic cytoreductive compounds); it is in general four and eight weeks respectively or more if dictated by toxicity.
Zinzani et al. Blood 1998;92:790-794. Pfreundschuh et al. Blood 2004; 104:626-633. Wunderlich
et al. Ann Oncol 2003;14:881-893; Gobbi et al. J Clin Oncol 2005; Prezpiorka et al. Ann Oncol 1999;10:527-532; Caballero et al. Bone marrow Transplant 1997;20:451-458; Weaver et al. Bone Marrow Transplant 1998;21:383-389; Martelli et al. J Clin Oncol 1996;14:534-542.
Cytotoxic cytoreductive compounds in intensive induction in myeloma contain in induction regimens among others vincristine, adriamycin, epirubicin, dexamethasone, cyclophosphamide, vincristine, prednison and monoclonal antibodies. Myeloma have always been poorly treated during the induction regimen; more aggressive treatment can induce higher response rates and cure. Dose density can be achieved by reducing the interval to two or three weeks. Semi-high-dose cytotoxic cytoreductive compounds are newly defined as half the reported dose of compounds in high-dose regimen; semi-high dose is this 100 mg/m2 melphalan. generally only melphalan is given. For more aggressive treatment compounds are added. Cycles with autologous stem cell rescue are given at 4 weeks interval. The general non-myeloablative reduced intensity conditioning regimen induces fast three lineage engraftment. The interval between the components of treatment is set (intensive induction and first semi-high-dose and last semi-high-dose and non-myeloablative reduced intensity combinations of cytotoxic cytoreductive compounds); it is in general four and eight weeks respectively or more if dictated by toxicity.
Alexanian et al. Am J hematol 1990;35: 194-8; Cavo et al. Blood 2005; 106:35-39. Segeren et al. Br J Haematol 1999;105:127-130; Egerer et al. Support Care Cancer 2001;9:380-385. Donehower et al. De Vuta, Hellman, Rosenberg, 4th ed. 1993, p410. Lopez perez et al. Bone Marrow transplant 2001;28:665-672; Lemioli et al. J hematother 1996;5:339-349.
Non-resectable or disseminated neuroblastoma are treated by chemotherapy; surgery is pursued to remove prior sides of major tumor burden. Subsequently megatherapy plus or minus bone marrow transplantation is the strategy that has been followed in the past, with consequently a lot of toxicity. The fact that surgery needs to be integrated in the therapy makes the situation complicated as wound cure will need to occur before the next chemotherapy cycle can be given. Combinations of cytotoxic cytoreductive compounds during induction contain among others alternating cycles of cisplatin and etoposide, cyclophosphamide and doxorubicin. Semi-high dose induction chemotherapy consists of combinations of cytotoxic cytoreductive compounds containing melphalan, carboplatin, etoposide with autologous stem cell rescue at four weeks interval by two semi-high-dose chemotherapy cycles will subsequently be given followed by non-myeloablative transplantation, eight weeks later unless toxicity dictates otherwise. Surgery upfront or after induction chemotherapy.
Frappaz et al. J Clin Oncol 2000; 18:339-349; Vater V et a;. Med Pediatric Oncol 1995;2491:217-224;Klingebiel et al. Eur J cancer 1998;3944: 13.98-1402.
Cytotoxic cytoreductive compounds in intensive induction in breast cancer contain in induction regimens among others fluorouracil, adriamycin, epirubicin, cyclophosphamide, taxol, docetaxel, and may be monoclonal antibodies. Dose density is achieved by admistering the combiantions at two weeks interval and, in general for four cycles f.e FEC 500/90-100/500
mg/m2. Semi-high-dose combinations of cytotoxic cytoreductive compounds are contain half the dose of reported containing among others cyclophosphamide, thiotepa, carboplatin, mitoxantrone, melphalan at four weeks interval with autologous stem cell rescue. CTCb is well known and reported at two high-dose level; thus tow semi-high doses are used. The general non- myeloablative reduced intensity conditioning regimen induces fast three lineage engraftment. The interval between the components of treatment is set (intensive induction and first semi-high- dose and last semi-high-dose and non-myeloablative reduced intensity combinations of cytotoxic cytoreductive compounds; it is in general four and eight weeks respectively or more if dictated by toxicity. The interval between the induction and semi-high-dose combinations is four weeks and between the latter and non-myeloablative reduced intensity conditioning eight weeks unless toxicity describes otherwise.
Van Hoef et al. Ann Oncol 1994;5:217-224; Van Hoef et al. Lancet 1992;34:1169-1190. Brufman et al. Ann Oncol 1997;8(2): 155-162; Marty M, et al. Eur J Cancer 1997;33(suρρl 7):D26-9; Nabholtz JM, et al. J Clin Oncol 2003;21(10):2048. Eder et al. J Clin Oncol 1990;8: 1239-45; Schrama et al. An Oncol 2002;13:650.
Often various high-doses have been described for the same combination of compounds; in such case semi-high-dosing is one of the described combinations of compounds.
Non-myeloablative reduced intensity conditioning regimens containing busulphan, fludarabine and cyclophosphamide or melphalan and fludarabine. We recommend the first which can be given on an outpatient basis and is associated with almost no graft failure. Our regimen is Busulphan/Cyclophophamide/fludrabine 8mg/kg/1050 mg/m2/120 mg/m2 over 2/3 and 3 days respectively. Another example is melphan/fludarabine 140/120 mg/m2. Busulphan/fludrabine/ATG is another regimen at a dose of 8mg/kg/180mg/m2/40mg/kg over in total ten days but CMV reaction by ATG has been reported. Allogeneic stem cells at the 108 CD8+ cells/kg dose level are infused after dosing.
Ruiz Arguelles et al.Hematology 2002;7:95-99; Or et al. Blood 2003; 101:414-445; Giralt et al.Blood 1997;89:4531-6; Korgsgaard et al Scand J Infect 1994;26:239-247.
GVHD prophylaxis is an integral part of allogeneic transplants; combination treatment is advised and defined in recommendations. Supportive care recommendations are given such as antiemetic, anti-infectives.
The manuals when protocols describe the objectives, study schedule and eligibility, response criteria, response assessment, study endpoint definitions, study endpoint assessment, donor criteria, clinical and laboratory assessment and other logistics. Studies are run through internet communication methods. Manual and protocols are distributed through sales.
The specific significance is in leukemia to give one to three of dose intensive remission induction courses, two consolidations courses, one of which is in the induction schedule, and a non-myeloablative reduced intensity conditioning course, all within a certain time frame. The
two consolidation courses enhance the response and make subsequent non-myeloablative reduced conditioning feasible; the CD8+ cell therapy adds the curative element.
The specific significance in semi-high-dosing is that such has not yet been reported to enhance the dose response and allow the subsequent non-myeloablative reduced intensity conditioning regimen within a certain time frame to ensure dose intensification; moreover, the two semi-high- dose combinations replace a high-dose autologous transplants and mimic together with the subsequent non-myeloablative transplant and ablative allogeneic transplants, though with much less toxicity. This sequence together with supportive measurements at diagnosis will likely cure >90 % of patients if the treatment is well performed.
For diseases such as early metastatic breast cancer that has yet only 10% 10 years survival the indication is clear a potentially curative treatment strategy with a probability of <5% treatment related mortality warrant studying; this also applies to several other malignant diseases and disease states mentioned herein. There are yet no data of any studies at diagnosis nor in high-risk lymph node postive breast cancer wherein likely >90% could survive instead of the current 60%.
Molecular remission of abnormalities detected in malignant disease can be monitored by immunohistochemistry, immunophenotyping or genotypic. A listing of chromosomal aberrations detectable in such manner can be found in text books as well as referral to detection methods. Disease present below the detection level is called complete remission; in such instance probability of relapse occurs without further treatment of which allogeneic immune competent cells are a critical element.
Integrated diagnosis treatment combinations are thus combinations of treatment modalities of which cytotoxic cytoreductive compounds, allogeneic immune therapy, hematopoietic stem cell rescue, supportive and prophylactic measures may be part. Surgery and radiotherapy may be part.
Examples of semi-high dose regimens cytarabine 8g/m2 and cytarabine/imatinib 8g/m2/400 mg/d for 14 days, cyclophosphamide/thiotepa/carboplatin 3000/250/400 mg/m2, cyclophosphamide/thiotepa/carboplatin 3000/240/800 mg/m2, cyclophosphamide/melphalan/carboplatin 3000/70/800 mg/m2
BCNU/Etoposide/Arabinoside/Melphalan 150/300/200/70 mg/m2 ,
BCNU/Etoposide/Arabinoside/Cyclophosphamide 150/300/200/3000 mg/m2, melphalan 100 mg/m2 melphalan/carboplatin mg/m2 and etoposide 20mg/kg
Claims
CLAIMS:
Claim 1): an integrated diagnosis treatment combination is comprised of independent therapeutic components including prophylactic and supportive measurements. The independent components may include induction combination therapy and/or an autologous transplant strategy and/or a non-myeloablative or reduced intensity conditioning allogeneic stem cell transplantation. Radiotherapy on bulk disease may be included, surgery may advance or be integrated. But may stay independent.
Claim 2): the method of claim 1, in malignant disease in the sequence of a) intensified induction therapy consisting of a combination of cytoreductive, cytotoxic and supportive compounds in dose dense intervals, b) an autologous transplant strategy consisting of semi-high-dose combinations of cytoreductive, cytotoxic compounds and supportive compounds/hematopoietic cells at intervals of weeks, c) an allogeneic stem cell transplant strategy consisting of non- myeloablative reduced intensity conditioning combinations of cytoreductive, cytotoxic compounds and prophylactic and supportive measurements and hematopoietic and immunocompetent cell grafting
Claim 3): The method of claim 2 whereby intensification in induction therapy is achieved by dose density defined as reduction of interval of combinations of compounds compared to standard interval and/or increase of dosing per combination of compounds compared to standard dose. This is important to reduce the development of tumor cell resistance and achieve high complete response rates.
Claim 4) The method of claim 2 whereby two semi-high-dose combinations of cytoreductive, cytotoxic compounds at an interval of weeks enhance the complete response rate of intensified induction therapy
Claim 5): The method of claim 2 whereby semi-high-dose combinations of cytoreductive, cytotoxic compounds eliminate treatment related mortality seen after high-dose combinations of cytoreductive, cytotoxic compounds in autologous transplantation.
Claim 6) The method of claim 4 whereby two semi-high-dose conditioning combinations of cytoreductive cytotoxic compounds with autologous stem cell rescue make subsequent non- myeloablative reduced intensity conditioning better feasible than high-dose conditioning, whereby semi-high-dose combinations are half the dose of described high-dose combinations..
Claim 7): The method of claim 6, whereby two semi-high dose combinations of cytoreductive, cytotoxic compounds at an interval followed by non-myeloablative reduced intensity combinations of cytoreductive, cytotoxic compounds prior to allogeneic stem cell infusion reduces overall treatment related mortality compared to conventional ablative cytoreductive, cytotoxic conditioning combinations of compounds in allogeneic transplantation.
Claim 8): The method of claim 7 whereby two semi-high dose conditioning combinations of
cytoreductive cytotoxic compounds with autologous stem cell rescue and non-myeloablative reduced intensity conditioning in allogeneic transplantation replaces conventional ablative conditioning in allogeneic transplantation.
Claim 9): The method of claim 8 whereby two semi-high dose combinations of cytoreductive cytotoxic compounds and non-myeloablative reduced intensity combinations of cytoreductive cytotoxic compounds in allogeneic transplantation at a fixed minimal interval replaces conventional ablative conditioning in allogeneic transplantation.
Claim 10): The method of claim 2 whereby combinations of cytoreductive cytotoxic compounds per component may be single compounds
Claim 11): The method of claim 2 whereby allogeneic hematopoietic and immune competent cell transplantation is responsible for sustained disease free survival above the disease free survival achievable by cytotoxic, cytoreductive compounds and supportive measurements.
Claim 12): The method of claim 12 whereby the stem cell sources is bone marrow, or mobilized peripheral blood progenitor cells or cord blood
Claim 13): The method of claim 12 where by the immune competent CD8+ cells in the allogeneic graft are responsible for the sustainability of complete remission. T-cell depletion is not appropriate.
Claim 14) The method of claim 2 also in breast cancer to cure above and beyond the currently pursued; metastatic breast cancer has always been undertreated.
Claim 15) The method of claim 2 also in myeloma to cure above and beyond the currently pursued; myeloma has always been undertreated.
Claim 16) The method of claim 2 also in lymphoma
Claim 17) The method of claim 2 also in neuroblastoma.
Claim 18): The method of claim 2 described in a manual
Claim 19): The method of claim 18 whereby the manual is used'as protocol
Claim 20) The method of claim 2 whereby the manual and/or protocol represent integrated diagnosis treatment combinations for implementation at a global level.
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| US8660800B2 (en) | 2007-09-04 | 2014-02-25 | Koninklijke Philips N.V. | Multi-treatment planning apparatus and method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8660800B2 (en) | 2007-09-04 | 2014-02-25 | Koninklijke Philips N.V. | Multi-treatment planning apparatus and method |
| US10521563B2 (en) | 2007-09-04 | 2019-12-31 | Koninklijke Philips N.V. | Multi-treatment planning apparatus and method |
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