Phase Of Hematopoietic Stem Cell Transplantation Research Articles

Increasing PatientÂʼS Trend Towards “Natural Comedication” - Supportive or Harmful in Transplantation? - A Case Report Documenting Sage to Severely Decrease Cyclosporine Bioavailability

Background: Intensified by influence of media there is an enormous trend towards additionally natural self-medication e.g. to cure with teas and drugs of natural resources seeming to be harmless even in most physiciansÂ'opinion. The transplant patient is at high risk to be affected by this modern way of co-treatment as well. E.g. we all are familiar with the herb-drug interaction resulting from St. John's wort. Experience and case report: In clinical pharmacology we are increasingly confronted with the question whether special natural agents the patients intend or started to supply themselves with in order to support or detox their existing medication may be associated with interactive potential. Esp. concerning therapeutic drug monitoring for immunosuppressants this aspect always needs being aware of. There are numerous natural agents we checked in detail via available literature throughout the last years concerning this problem. From these data it is recommended to be more cautious than most patients and physicians tend to be. Most of the agents are classified as safe concerning interactions despite lacking data whether they have been checked adequately or not. As an impressive own example we report on our recent finding in a male patient (P) 24yrs of age being within the earliest very sensitive phase of hematopoietic stemcell transplantation. He is on a standard therapeutic regimen including cyclosporine (CSA) achieving stable trough levels within therapeutic range (˜ 250ng/ml) with a twice daily dosage of 175mg intravenously. On day 4 his CSA trough level decreases to subtherapeutic132ng/ml, daily increasing dose adjustment becomes necessary to recover from this severe decrease and there is no agent within comedication that can be identified to be responsible for this phenomenon e.g. as an enzyme inducer. Our insisting inquiries at least reveal the P himself started to drink concentrated sage tea (salve) to overcome severe mucositis induced by preceeding conditioning regimen. To achieve therapeutic CSA trough levels the dosage almost needs being doubled (1.9 fold; 325 mg intravenously twice daily = 650mg vs. 350 mg/day). Without any evidence from literature we ask to stop ingestion of sage tea yet. This intervention results in increasing CSA exposure again as the P presented prior to sage consumption indicating recovering from sage-CSA interaction. The close drug-monitoring again documents to be the only reliable indicator to enable earliest adaption in decreasing trough blood levels of immunosuppressants as CSA which in this context is regarded as being almost entirely checked concerning clinically relevant drug-drug or herb-drug interactions. It might have protect the P from graft versus host disease or even lethal failure of engraftment. Conclusion: 1. It is a recommending challenge always to search for the reason for inadequate alterations of trough blood levels. 2. Sage seems to have an interactive potential with CSA. 3. Further investigation of sage which includes more than 60 ingredients is required to elucidate the mode of sage-CSA interaction e.g. via CYP3A4 inducer or P-glycoprotein or both resp. 4. This mechanism probably might be the same with tacrolimus and mTORinhibitors because of their analogous metabolism.

A Brief Use of Imatinib Immediately Before Hematopoietic Stem Cell Transplantation (HSCT) in Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph+ALL04

Abstract▪2554▪This icon denotes a clinically relevant abstract Aims:Children with Ph+ALL generally have a poor prognosis when treated with chemotherapy alone. The timing and duration of the use of imatinib has not been determined. We investigated a role of imatinib immediately before HSCT. Methods:All the patients with ALL were screened for diagnosis of Ph+ALL using RT-PCR. Children with Ph+ALL were enrolled on JPLSG Ph+ALL04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of 5 therapeutic phases: Induction phase (5-drug induction), Intensification phase (high-dose cytarabine and BFM Ib), Re-induction phase (4-drug re-induction), 2 weeks of Imatinib monotherapy phase (23 weeks after diagnosis), and HSCT phase (Etoposide+CY+TBI conditioning). Before and after each phase, minimal residual disease (MRD), the amount of BCR-ABL transcripts, was measured with the real-time PCR method (cut-off 50 copies/microgram RNA). The study was registered in UMIN-CTR (Medical Information, University hospital Medical Information Network - Clinical Trials Registry): UMIN ID C000000290. Results:During the period 2004–08, 42 patients were registered in the Ph+ALL04 study. Out of 42 patients, 37 patients (88%) achieved CR and 7 of 37 patients also achieved MRD-negative after induction phase. There were 13 patients who had no MRD at the beginning of imatinib monotherapy phase, and 14 patients were MRD-negative after imatinib phase, consequently, 14 patients were MRD-negative at the time of HSCT. Six patients relapsed before HSCT. In total, 31 patients received HSCT in 1st CR. All the patients had engraftment and no patients died because of complications of HSCT. Five patients relapsed after HSCT and 4 of the 5 patients were MRD-negative before HSCT and the other patient had detectable MRD although it was less than 50 copies. Twenty-six patients continue to be in 1st CR and MRD-negative for median of 3 years after diagnosis. The 3-year event-free survival rate and over-all survival rate for all the patients was 57% and 80%, respectively (figure 1). Five patients did not achieve CR after induction phase and they were treated with imatinib-contained chemotherapy. Four of the 5 patients achieved CR. All of the 4 patients received cord blood transplantation and remains in continued CR. Interpretation:The chemotherapy we employed was based on the previous high-risk regimen of TCCSG (Tokyo Children’s Cancer Study Group) L-99-15 Study. The chemotherapy was intensive enough to induce MRD-negative in 13 at the time of imatinib phase and 31 of 42 patients were in CR at the time of HSCT (around 25–28 weeks after diagnosis). We planned to assess the efficacy of imatinib immediately before HSCT but it was not possible because of the low amount of MRD in most patients at the beginning of imatinib phase. Conclusion:Although EFS and OS was excellent in this study, 88% of induction rate appeared unsatisfactory and relapse occurred before HSCT in 6 out of 37 patients who achieved CR after induction phase. Earlier and longer use of imatinib may improve EFS in children with Ph+ALL and HSCT may be omitted in a subset of patients who achieve an early and deep remission status. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Minimal Risidual Disease monitoring in Childhood Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia: Preliminary Results of JPLSG Ph+ALL04.

Abstract 4116Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) is very rare and poor prognostic condition in children. Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted first nationwide clinical trial for Ph+ALL in children (Ph+ALL04). Ph+ALL04 consists of five therapy phases; Induction phase (five drugs induction), Intensification phase (high-dose CA and BFM Ib), Re-induction phase (four drugs re-induction), Imatinib mono-therapy phase, and hematopoietic stem cell transplantation phase (VP+CY+TBI condioning). Before and after each phase, BCR-ABL minimal residual disease (MRD) was monitored by the real-time PCR method. During the period 2004-08, 44 patients were enrolled in the Ph+ALL04 study. Out of 44 patients, five were resistant to Induction Phase and did not achieve CR. Their levels of BCR-ABL transcript at diagnosis were significantly higher than that of patients achieved CR after Induction phase. After Induction phase, 39 patients achieved CR, and seven of 39 patients also achieved MRD negative. After Intensification phase, two patients relapsed. Thirty-four patients were still in CR, and 10 patients also achieved MRD negative after Intensification phase. One patient relapsed after Re-induction phase and three patients relapsed after Imatinib mono-therapy phase. Thirteen patients were MRD negative before Imatinib mono-therapy phase, and 14 patients were MRD negative after Imatinib mono-therapy phase. Before Hematopoietic stem cell transplantation phase, 14 patients were MRD negative. Twenty-six patients received hematopoietic stem cell transplantation. Out of 26 patients, three relapsed after hematopoietic cell transplantation. Twenty-three patients continued to be in CR and MRD negative for median 2 years after hematopoietic stem cell transplantation. In conclusion, amount of BCR-ABL transcript is a possible predictor for achieving remission after induction therapy in Ph+ALL children. MRD detection during therapy is confirmed the important prognostic indicator in the context of the intensive chemotherapy and hematopoietic stem cell transplantation in Ph+ALL children. Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation Phase III Clinical Trials for Patients with Hematological Malignancies in the US: Lessons To Be Learned from the European Experience.

Introduction: Evidence-based medicine defines standard therapies primarily from Phase III randomized controlled trials (RCT), when available. In this report we examined trends in ther number and characteristics of phase III RCT addressing the management of adult patients with hematological malignancies, comparing the patterns of activity in the US and Europe. Materials and Methods: We attempted to identify all phase III RCT published in the English medical literature from 1/1992 to 12/2003. A systematic search of Medline and published references was conducted using multiple keywords for each malignancy as well as for hematopoeitic stem cell transplant (HSCT). We cross-referenced the data by searching individual journals, as well as the ASH education books from 1998–2003. Studies published in abstract form only were not included. Results: We identified 306 published RCT that accrued a total of 4899 patients. Eighty-three of these studies included HSCT with a total accrual of 2081 patients. Country of origin included: US (n= 25), Europe (n=54), other (n=4). Four European countries (France, Italy, Germany and UK: FIGU) with a combined population similar to that of the US produced 32 studies. This figure for FIGU does not include their contributions to 12 separate European cooperative trials. There were no significant trends in the number of trials published per year during the study period. However, significant differences emerged when the focus of the studies and the accrual numbers were analyzed. RCTs comparing HSCT to standard dose therapy represented 34.9% of the 83 trials and 59.4% of FIGU trials, but only 4% (1 out of 25) of US studies (p <.001). US trials accrued a mean of 110.2 patients per study, as compared to 205.3 in other countries and 222.6 in FIGU studies (p= .006). In multivariate analysis, only focus of study was independently related to greater study size (p<.001). Among the remaining 223 trials not involving HSCT (US produced 68 and FIGU 77), a significant trend for increasing numbers of trials published per year during the study period was documented (p=.015). No significant differences in the mean number of patients accrued per trial (US= 279.5, other countries= 302.8 and FIGU= 347.8), or in the focus of the studies were observed in univariate or multivariate analysis. Conclusions: While there has been an increase in the number of Phase III RTCs in patients with hematological malignancies published during 1992–2003, the activity for HSCT trials has remained stationary. US HSCT trials have focused on issues other than the comparison of HSCT to standard therapies, such as graft manipulation, growth factors and graft versus host disease. US HSCT have accrued significantly fewer patients per study. The reasons for these differences are not apparent from our data, and may include patient and/or physician attitudes/biases toward phase III trials, issues of financial coverage for the HSCT procedure and/or health care delivery policies. There is a serious paucity of US trials defining the role of HSCT in the management of hematological malignancies.