The clinical pharmacology of alkylating agents in high-dose chemotherapy

2000 ◽  
Vol 11 (7) ◽  
pp. 515-533 ◽  
Author(s):  
Alwin DR Huitema ◽  
Karen Doesburg Smits ◽  
Ron AA Mathôt ◽  
Jan HM Schellens ◽  
Sjoerd Rodenhuis ◽  
...  
Keyword(s):  
Clinical Pharmacology ◽  
Alkylating Agents ◽  
High Dose Chemotherapy ◽  
High Dose

Rituximab in Anti-Mag Associated Neuropathy : A Monocentric Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4909-4909
Author(s):  
Richard Delarue ◽  
Benedicte Deau ◽  
Marie-Alexandra Alyanakian ◽  
Bruno R. Varet ◽  
Olivier Hermine
Keyword(s):  
Stem Cell ◽  
Case Reports ◽  
Alkylating Agents ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Mild Improvement ◽  
Sensory Motor ◽  
Anti Cd20 ◽  
High Dose Melphalan ◽  
Monoclonal Component

Abstract Anti-MAG associated neuropathy is a rare disorder characterized by a sensory-motor polyneuropathy in the context of monoclonal IgM, which activity is directed against myelin-associated glycoprotein on the surface of myelin sheaths. Treatments are usually ineffective. Most common therapy is based on alkylating agents such as Chlorambucil, which however only rarely improve neurological tests nor induce disappearance of monoclonal component. More recently, the benefit of monoclonal anti-CD20 antibody Rituximab was reported in case reports. Thus, we have performed since 2002 a prospective pilot study to assess the benefit of Rituximab in anti-MAG associated neuropathy. We report here the first four successive patients treated. Patients and Methods : inclusion criteria were as follow : peripheral sensory-motor polyneuropathy with clinical and electrophysiological symptoms compatible with anti-MAG associated neuropathy; serum monoclonal IgM; serum anti-MAG reactivity; absence of other cause of peripheral neuropathy such as amyloidosis; absence of underlying condition contra-indicating Rituximab therapy. Patients received 4 courses of Rituximab (375 mg/m2) with a 7 days interval between two infusions. Usual premedication with corticosteroids and paracetamol were administered. Evaluation of clinical, biological and immunochemical efficiency was performed every three months. Results : characteristics of the first four patients treated are as follow : 3 males and 1 female; median age : 65 years (57 – 87); median time between onset of symptoms and Rituximab therapy : 4 years (3 – 6). Previous treatments were Chlorambucil (3/4), corticosteroids (2/4), intravenous Ig (1/4), anthracyclin-containing regimen (1/4), plasmapheresis (1/4). All were ineffective. Rituximab was well tolerated by all patients. Median follow-up after treatment is 2 years (1 – 3). None of the patients exhibit improvement of clinical neurological symptoms. Electrophysiological evaluation show only a mild improvement in 1 patient. Moreover, no decrease in monoclonal component nor disappearance of anti-MAG reactivity of serum were observed in any cases. Interestingly, one patient exhibited later neurological and biological improvement after high dose Melphalan followed by autologous stem cell transplantation. Conclusion : Rituximab monotherapy does not seem to improve neurological outcome of patients with anti-MAG polyneuropathy as well as is unable to clear serum from monoclonal IgM. Therefore, new approaches are needed, for example with high dose chemotherapy with stem cell support in selected patients.

Oral Etoposide for Refractory and Relapsed Neuroblastoma

1999 ◽  
Vol 17 (10) ◽  
pp. 3221-3225 ◽  
Author(s):  
Brian H. Kushner ◽  
Kim Kramer ◽  
Nai-Kong V. Cheung
Keyword(s):  
Residual Disease ◽  
Alkylating Agents ◽  
High Dose Chemotherapy ◽  
Treatment Programs ◽  
Induction Treatment ◽  
High Dose ◽  
Oral Etoposide ◽  
Disease Markers ◽  
Stage 4 ◽  
Dose Oral

PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m2 taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m2 to 3,935 mg/m2 (median, 2,300 mg/m2). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.

scholarly journals SS-5 Current management of primary central nervous system lymphoma

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii2-ii2
Author(s):  
Kazuhiko Mishima ◽  
Mitsuaki Shirahata ◽  
Junichi Adachi ◽  
Tomonari Suzuki ◽  
Eita Uchida ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Standard Dose ◽  
Alkylating Agents ◽  
Central Nervous System Lymphoma ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
Common Adverse Event ◽  
High Dose ◽  
Newly Diagnosed

Abstract Primary CNS Lymphomas (PCNSLs) is a highly aggressive malignant tumor with poor prognosis and increasing incidence in elderly patients. High-dose methotrexate (HD-MTX) followed by whole-brain radiation therapy (WBRT) improves survival in PCNSLs. Several HD-MTX–based regimens, in combination with alkylating agents and rituximab, have been developed that can achieve high and durable complete response rates in patients with newly diagnosed PCNSL. In Japan, the R-MPV regimen using rituximab, HD-MTX, procarbazine, and vincristine has been recognized as the standard treatment for initial induction for newly diagnosed PCNSL. The optimal consolidative therapy for patients with disease responsive to induction chemotherapy is not yet defined. WBRT at standard dose (30–45 Gy) has a risk of neurotoxicity. To minimize the effects of delayed neurotoxicity, high-dose chemotherapy supported by autologous stem cell transplantation, reduced dose WBRT (23.4Gy), non-myeloablative chemotherapy, and maintenance chemotherapy have been addressed in large randomized trials. Gene expression profiling has provided insights into the pathogenesis of PCNSL. Recent insight into the pathophysiology of PCNSL has led to the investigation of targeted agents in the treatment of recurrent disease. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for relapsed or refractory PCNSL based on the results of the phase I/II study in Japan. Seventeen of 44 patients treated with TIR at 480 mg fasted QD, an approved dose, had overall response rate of 52.9%, median progression-free survival of 5.8 months, and time to response as short as 0.92 months. The most common adverse event at any grade was rash (32%). The skin-related disorders were manageable with appropriate skin treatments. However, greater attention and management is needed the case of more rare adverse events such as severe skin-related disorders and pneumocystis pneumonia. This lecture aims to present the recent development in treatment for PCNSL.

High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer.

1988 ◽  
Vol 6 (9) ◽  
pp. 1368-1376 ◽  
Author(s):  
W P Peters ◽  
E J Shpall ◽  
R B Jones ◽  
G A Olsen ◽  
R C Bast ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Metastatic Breast Cancer ◽  
Median Duration ◽  
Alkylating Agents ◽  
Metastatic Breast ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Single Treatment

To evaluate the effect of high-dose chemotherapy in the treatment of metastatic breast cancer, we performed a phase II trial of a single treatment with high-dose cyclophosphamide (5,625 mg/m2), cisplatin (165 mg/m2), and carmustine (600 mg/m2), or melphalan (40 mg/m2) and bone marrow support as the initial chemotherapy for metastatic breast cancer. Twenty-two premenopausal patients with estrogen receptor negative, measurable metastatic disease were treated. Twelve of 22 patients (54%) obtained a complete response at a median 18 days. The overall response rate is 73% (complete and partial response). Median duration of response in the patients achieving complete response was 9.0 months with a median duration of survival for complete responders that is currently undefined. Relapse occurred predominantly at sites of pretreatment bulk disease or within areas of previous radiation therapy. Toxicity was frequent and five patients died of therapy-related complications. The results indicate that a single treatment with intensive combination alkylating agents with bone marrow support can produce more rapid and frequent complete responses than conventional chemotherapy when used as initial chemotherapy for metastatic breast cancer, although median disease-free and overall survival is not improved. Three patients (14%) remain in unmaintained remission beyond 16 months.

Comparison of Two Alkylating Agents Among Refractory Multiple Myeloma: Published and Our Retrospective Bendamustine Combination Experience with Melflufen As Single Agent

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Ekin Kircali ◽  
Guldane Cengiz ◽  
Sevgi Çolak ◽  
Mehmet Gunduz ◽  
Pinar Ataca Atilla ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Research Funding ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Single Agent ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Refractory Multiple Myeloma ◽  
Support Research

Introduction: Bendamustine is a synthetic alkylating agent made of both mustard and benzimidazole groups. It is used mainly in myeloma patients who have run out of classical treatment options and yet, have eligible performance status. Although data is still accumulating, there is not enough information to recommend a certain standard bendamustine dose or regimen in multiple myeloma. Melflufen is also an alkylator that is activated once metabolized by peptidases [1]. The logic this molecule selects and exterminates myeloma tumor cells by is that, myeloma cells overexpress aminopeptidases. Here, we have compared our and published bendamustine combination with melfufen data. Methods: We retrospectively analyzed our relapsed or refractory multiple myeloma patients who received bendamustine between 2002 and 2020 at Ankara University Medical School. All statistical analyses were performed via SPSS statistics version 20.0 software. After Pubmed search, all published bendamustine combination and melflufen clinical data among relapse refractory myeloma patients were included in the analysis. Results: Female/ male ratio was 14/ 18 (43.7 % / 56.3 %). Median age was 62 (36- 77) years. 22 (68.7 %) patients had Ig G myeloma, 6 (18.7 %) had Ig A myeloma and 4 (12.6 %) had light chain myeloma. ISS scores were as follows: I/ II/ III: 8 (25 %)/ 17 (53.1 %)/ 7 (21.9 %). FISH defined cytogenetics were available for 18 patients; 8 of them had normal chromosome analysis, 3 had only del13q, 1 had tri7. High risk cytogenetics was observed among 6 (33.3 %). R-ISS scores were as follows: I/ II/ III: 4 (22.2 %)/ 12 (66.7 %)/ 2 (11.1 %). Median prior lines of therapy was 3 (1- 6). 30 (93.8 %) patients had a history of bortezomib, 21 (65.6 %) had lenalidomide, 9 (28.1 %) had thalidomide. 21 (65.6 %) patients had undergone high-dose chemotherapy supported by autologous stem cell transplantation before bendamustine. 15 (46.9 %) patients were in treatment- refractory status at bendamustin initiation while 17 (53.1 %) used it for disease progression. Bendamustin was given either with Dexa (n= 13, 40.6 %) Bortezomib+ Dexa (n=6, 18.8 %), Lenalidomide+ Dexa (n=6, 18.8 %), Pomalidomide+ Dexa (n=5, 15.6 %) or Thalidomide+ Dexa (n= 2, 6.3 %). Bendamustine dose was 100- 120 mg/ m2/ day, 2 days monthly. 32 patients were followed up for median 26 months. Response to bendamustine treatment were as follows: Complete remission 4 (12.5 %), very good partial response 12 (37.5 %), partial response 8 (25 %), unresponsive 8 (25 %). Median progression free survival (PFS) was 5.6 (1- 40.6) months and overall survival (OS) was 17.3 (2- 79) months with bendamustine based treatment protocols. 15 (46.9 %) patients suffered grade ≥3 myelosuppression. Febrile neutropenia was experienced by 7 (21.9 %) patients, and 6 (18.7 %) had CMV reactivation during bendamustine treatment. There was no drug related mortality. Conclusion: Although bendamustine is effective among highly refractory myeloma patients, toxicity profile and immune plus myelosuppression prevents long term use. Bendamustine in our experience in combination has provided efficacy comparable to earlier publications. Current single agent Melflufen data in advanced stages may be even more promising if combined with proteasome inhibitors or IMIDs. References 1. Richardson, P.G., et al., Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study. The Lancet Haematology, 2020. 2. Knop, S., et al., The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. haematologica, 2005. 90(9): p. 1287-1288. 3. Grey-Davies, E., et al., Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. British journal of haematology, 2012. 156(4): p. 552-555. 4. Damaj, G., et al., Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program. Leukemia & lymphoma, 2012. 53(4): p. 632-634. 5. Ludwig, H., et al., Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood, The Journal of the American Society of Hematology, 2014. 123(7): p. 985-991. Disclosures Ozcan: Abdi Ibrahim: Other; Archigen Biotech: Research Funding; Amgen: Honoraria, Other: Travel support; Bristol Myers Squibb: Other: Travel support; Jazz Pharmaceuticals: Other; Sanofi: Other; F. Hoffmann-La Roche Ltd: Other: Travel support, Research Funding; Celgene: Research Funding; MSD: Research Funding; Janssen: Other: Travel support, Research Funding; AbbVie: Other: Travel support, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding.

Experience with Autologous HSC Transplant in Therapy-Related MDS/AML Using Cells Harvested Prior to the Development of the Secondary Malignancy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5099-5099
Author(s):  
Luciano J. Costa ◽  
Vilmarie Rodriguez ◽  
Luis F. Porrata ◽  
Martha Q. Lacy ◽  
Michelle A. Elliott ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Topoisomerase Ii ◽  
Alkylating Agents ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Secondary Malignancy ◽  
High Dose ◽  
Primary Malignancy ◽  
Curative Intent ◽  
Non Hodgkin Lymphoma

Background: Therapy-related MDS/AML (t-MDS/AML) is a common and devastating complication of treatment with alkylating agents and topoisomerase II inhibitors, often employed with curative intent, in standard or high-doses, in the treatment of hematological malignancies and solid tumors. Allogeneic HSC transplant is considered the standard treatment for t-MDS/AML but its applicability is limited by the unavailability of donors, comorbidities in the recipient and risk of acute and chronic graft-versus-host disease. Patients carrying diseases commonly treated with high-dose chemotherapy and autologous HSC transplant (such as multiple myeloma and non-Hodgkin lymphoma) who latter develop t-MDS/AML occasionally have stored HSC harvested prior to the diagnosis of the secondary malignancy (hereafter called early-stored HSC). The benefit of using early-stored HSC to support myeloablative therapy for the treatment t-MDS/AML is unknown. Methods: Retrospective, single center analysis of patients with t-MDS/AML receiving myeloablative chemotherapy with or without irradiation supported with early-stored HSC. Results: Six patients received early-stored HSC transplant for treatment of t-MDS/AML between 2000 and 2007. Median age at the time of the transplant was 57 years (range 15–71). Three patients had been primarily diagnosed with follicular lymphoma, 2 with multiple myeloma and 1 with Ewing’s sarcoma. One patient had received prior autologous HSC transplantation. Two patients developed AML, 1 patient CMML, 1 patient RCMD, 1 patient RAEB1 and 1 patient RAEB2. Median time from diagnosis of primary malignancy to HSC harvesting was 26 (2–122) months and from harvesting to development of t-MDS/AML 44 (7–79) months. Conditioning regimen was Cy/TBI in three patients, BuCy in 2 patients and Samarium + Melphalan in one patient. Five patients engrafted neutrophils and 4 patients engrafted platelets 10–34 and 13–126 days after transplant respectively. In 3/6 patients there was disappearance of the pre-transplant chromosomic abnormality (2 patients -7 and 1 patient -7 and t(1;7)). Two patients obtained hematologic CR and two patients obtained CR without full recovery of platelets. One patient died of sepsis 230 days after transplant, one died with refractory disease on day 103 after transplant and one patient is alive with recurrence of t-MDS. Three patients are alive and free of disease 7, 73 and 87 months after transplant. Conclusion: Myeloablative conditioning followed by autologous, early-stored HSC transplant can provide prolonged survival to patients with tMDS/AML not suitable to allogeneic SCT.

High-dose chemotherapy and hematopoietic stem cell transplantation for breast cancer: Past or future?

2001 ◽  
Vol 28 (4) ◽  
pp. 377-388 ◽  
Author(s):  
Roy D. Baynes ◽  
Roger D. Dansey ◽  
Jared L. Klein ◽  
Caroline Hamm ◽  
Mark Campbell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem

Gamma knife radiosurgery in patients with advanced breast cancer undergoing bone marrow transplant

2002 ◽  
Vol 97 ◽  
pp. 663-665 ◽  
Author(s):  
Kenneth J. Levin ◽  
Emad F. Youssef ◽  
Andrew E. Sloan ◽  
Rajiv Patel ◽  
Rana K. Zabad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Gamma Knife ◽  
Gamma Knife Radiosurgery ◽  
High Dose Chemotherapy ◽  
Advanced Breast ◽  
High Dose ◽  
Initial Management ◽  
Content Type ◽  
Fine Print

Object. Recent studies have suggested a high incidence of cognitive deficits in patients undergoing high-dose chemotherapy, which appears to be dose related. Whole-brain radiotherapy (WBRT) has previously been associated with cognitive impairment. The authors attempted to use gamma knife radiosurgery (GKS) to delay or avoid WBRT in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow transplantation (HDC/ABMT) in whom brain metastases were diagnosed. Methods. A retrospective review of our experience from 1996 to 2001 was performed to identify patients who underwent HDC/ABMT for advanced breast cancer and brain metastasis. They were able to conduct GKS as initial management to avoid or delay WBRT in 12 patients following HDC/ABMT. All patients were women. The median age was 48 years (range 30–58 years). The Karnofsky Performance Scale score was 70 (range 60–90). All lesions were treated with a median prescription dose of 17 Gy (range 15–18 Gy) prescribed to the 50% isodose. Median survival was 11.5 months. Five patients (42%) had no evidence of central nervous system disease progression and no further treatment was given. Four patients were retreated with GKS and three of them eventually received WBRT as well. Two patients were treated with WBRT as the primary salvage therapy. The median time to retreatment with WBRT was 8 months after the initial GKS. Conclusions. Gamma knife radiosurgery can be effectively used for the initial management of brain metastases to avoid or delay WBRT in patients treated previously with HDC, with acceptable survival and preserved cognitive function.

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