Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1046
`
`Exh. 1046
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`

`
`350b
`Abstract# 5167
`Outcomes of Stem Cell Transplant Recipients Requiring
`Mechanical Ventilation and Cared for
`in the Bone Marrow
`Transplant Unit. Omanlyi Omotoso*, Hanna Khoury, Doug Adkins,
`William Blum, Manuel Iregui*, Peter Westervelt, Ravi Vij, Randy Brown,
`Lawrence Goodnough, John DiPersio. Bone Marrow Transplantation and
`Leukemia, Washington University School of Medicine, St. Louis, MO, USA.
`The outcome of stem cell transplant (SCT) recipients admitted to the medical intensive
`care unit (MICU) has been well documented with reported survival rates of 10-18% (Ann
`Int Med 1996; 125:625). We sought to determine, in a single centre, the outcomes ofSCT
`recipients requiring intubation and mechanical ventilation and who were nursed in
`designated ICU rooms within the BMT unit. Between May 1996 and March 2001, 1,269
`patients received SCT at Washington University in St-Louis, and 59 (4.6%) required
`intubation and mechanical ventilation. Patients characteristics were as follows: median
`age was 46 years (range, 19-66); diagnoses included acute and chronic leukemias (n=25,
`42%) and non-leukemic malignancies (n=34, 58%). Twenty patients (34%) received
`autologous SCT, while 21 (36%) received allogeneic SCT from a matched sibling donor and
`18 (30%) from a matched unrelated donor. TBI was included in the conditioning in 68%
`(n=40). Median time from SCT to intubation was 19 days (range, 0 -1351), and median
`duration of intubation was 5 days (range,l-38 days). Infectious complications (sepsis,
`pneumonia) were the most common indications for intubation (94% ). Kaplan-Meier estimates
`for survival I month, 3 months and 1 year post-intubation were 25%, 24% and 21%,
`respectively. Variables associated with poor outcomes were analyzed. The presence of
`hyperbilirubinemia (serum bilirubin >3mg/dl) or renal dysfunction (creatinine >2 mg/dl)
`24 hours prior to intubation, or an APACHE III score> 75 determined 24 hours post-
`intubation were associated with a 0% extubation rate and survival. Only 1118 unrelated
`donor transplant recipient survived. In summary, our results show that the management of
`SCT recipients requiring intubation and mechanical ventilation is feasible in the BMT unit
`and is associated with a similar survival to patients transferred to the MICU. Nursing these
`patients in the BMT unit offers family members uninterrupted access to the patient, comparable
`outcomes to those observed in the MICU and continuous accessibility to BMT trained
`health care personnel.
`
`Abstract# 5168
`Pediatric Hematopoetic Stem Cell Transplantation (HSCT) in the
`Chilean Public Health System: Initial Experience. J. Palma*, C.
`Mosso*, M. Campbell*, C. Salgado*, L. Vargas*, A. Becker*, P. Advis*, J.
`Quintana*, H. Garcia*, V. Beresi*. (Intr. by Gaston K. Rivera) PINDA
`(Programa Infantil Nacional de Drogas Antineoplasicas) and Hospital
`Luis Calvo Mackenna, Santiago, Chile.
`The national pediatric oncology cooperative group in Chile, PINDA, was founded 14
`years ago. Initially, HSCT was not available to patients locally. With combined efforts from
`PINDA and St. Jude Children's Research Hospital in Memphis, TN, USA, in October 1999
`a transplant unit was opened at Hospital Luis Calvo Mackenna, a public pediatric center
`with affiliation to the University of Chile. Eligible for transplantation, at no cost to their
`families, were all children treated at PINDA institutions. We report results for the initial21
`HSCT procedures performed: 18 allogeneic ( 17 matched-sibling and one haplotype-matched
`parent), and 3 autologous. Median age at the time ofHSCT was 6 years (0.5-17 years).
`Diagnoses included CML (n=2), AML CR 1, 2 (n=4), ALL CR 1, 2, 3 (n=4), Hodgkin (n=1 ),
`neuroblastoma IV (n=l), severe aplastic anemia (n=6), Kostmansyndrome (n=1), and SCID
`(n=1). Chemotherapy was given as preparative regimen in 9 allogeneic and 2 autologous
`HSCT; chemotherapy and total body irradiation in 5 and with total nodal irradiation in an
`additional5 cases. The median CD34 cell count was 2.64 x 106/kg (range, 1.31 to 7.2x106/
`
`kg) when marrow cells were infused and 5.68 x 106 (range, 3.26 to 9 .09xl 06) when peripheral
`blood cells were used. Heparin prophylaxis for venoclusive disease (VOD) was given to all
`patients from day -7 to +21 and cyclosporine was administered to patients who received
`allogeneic HSCT. Neutrophil counts were recovered at a median time of 19.3 days (range, 9-
`34), platelets 19 days (range, 12-42) and reticulocyte counts were> 1% at 17.4 days (range,
`11-34). Only 4 children had documented bacteremia, 3 developed grade III-IV graft vs. host
`disease, and no patient had VOD or required mechanical ventilation. There were no transplant
`related deaths. One patient died following disease relapse. All other patients are clinically
`well. Fifteen of 15 patients showed donor engraftment as indicated by molecular testing.
`Costs with up to 2 years of follow-up were $20,000 for autologous and $40,000 for allogeneic
`cases. The ongoing results show acceptable rates of morbidity and.mortality and an
`encouraging outcome. Since these results are comparable to those obtained at international
`centers, we demonstrate that HSCT can be successfully performed, and at reduced costs,
`within the public health system of developing nations.
`
`Abstract# 5169
`An Interesting 5-HT 3 Receptor Antagonist Antiemetic for Patients
`Undergoing Chemotherapy-Based Conditioning Regimens? Gaia
`Piraccini*, 1 Randall Stolz*,2 Munetetsu Tei*,3 Steve Chemoff*.4 (lntr. by
`John C. Byrd) 1Helsinn Healthcare SA, Lugano, Switzerland; 2GFI
`Pharmaceutical Services, Evansville, IN, USA; 3School of Medicine,
`University of Tokyo, Tokyo, Japan; 4US Micron, Lenexa, KS, USA.
`Palonosetron is a potent, highly selective 5-HT3 receptor antagonist with a strong
`binding affinity, long half-life and a low incidence of side effects. It does not exist as a racemic
`mixture as do other 5-HT3 antagonists but rather as a single stereoisomer. Five Phase I
`studies evaluated the pharmacokinetic and metabolic profile of palonosetron. Two studies
`used the IV formulation with dose ranges of0.3-90 meg/kg, while two studies used the oral
`formulation with dose ranges of 3-90 meg/kg. The fifth study used [14C]-palonosetron to
`determine the metabolic profile and pharmacokinetics in plasma and urine. The studies
`showed that 62% of palonosetron is protein bound. The liver metabolizes approximately
`
`CLINICAL CARE- TRANSPLANTATION REGIMEN TOXICITIES AND ENGRAFTMENT
`50% of the drug with 40% found unchanged in the urine. The most interesting characteristic
`however, is the long half-life. The elimination half-life is about 40 hours, which is longer
`than any other available 5-HT3 receptor antagonist (range 5.5-9 hours). There were no
`unexpected treatment emergent adverse events, nor were there any serious adverse events
`seen in the 173 subjects evaluated for safety. The most common adverse events were headache
`and constipation ( 6% and 11% respectively over the placebo rate), generally mild to moderate.
`Adverse events were not dose related. The strong binding affinity coupled with the chemical
`characteristics of the molecule may explain its high potency. Similarly, since a long duration
`of action may result from the long half-life and strong binding affinity, a Phase II dose
`ranging study was initiated. The study was designed to evaluate approximately 150 patients
`receiving highly emetogenic chemotherapy. Patients were assigned to one offive (5) dose
`groups of IV palonosetron while undergoing highly emetogenic chemotherapy including
`cyclophosphamide. Patients were evaluated for efficacy including duration of action, safety
`and pharmacokinetics for prevention of both acute emesis as well as emesis occurring on
`days 2-7. The encouraging pharmacokinetic results from five Phase I trials of palonosetron
`provided a basis to design the previously described Phase II dose ranging trial. This trial
`would evaluate the potential benefit of palonosetron for the prevention of nausea and
`vomiting in patients, including those receiving multi-day stem cell transplantation
`conditioning regimens.
`
`Abstract# 5170
`Effect of Bowel Preparation in Patients Undergoing HDSCT in a
`Community Hospital Setting. Anastasios Raptis, 1 Oscar Ballester,2
`Bradford Tan*, 1 Patti Wilcox*, 1 James Grutsch*, 1 Brian Braun*. 1 1Bone
`Marrow Transplant Program, Midwestern Regional Medical Cente1; Zion,
`JL, USA; 2Bone Marrow Transplant Program, Albany Medical Cente1;
`Albany, NY, USA.
`Infection is an important complication of patients undergoing high dose chemotherapy
`and stem cell transplantation (HDSCT), contributing significantly to the morbidity and
`mortality associated with the procedure. In an effort to reduce the prevalence of developing
`bacterial infection in this group of patients, physicians at MRMC-CTCA developed a
`protocol using the product GoLYTELY®(GT) to prepare the patient's bowel prior to stem
`cell transplantation. We evaluated the hypothesis that the GT treatment reduced the
`prevalence of positive bacterial cultures. At MRMC-CTCA 141 patients underwent HDSCT
`between September of 1994 and December of2000. Forty-four patients received one gallon
`of GT once, one day prior to initiation of high dose chemotherapy (group A). Ninety-four
`of the patients received no GT (group B). There was no difference in the age distribution
`between group A and group B, 48 and 50.2 respectively (Median test two tailed p =
`0.37).Patients with the following diagnoses received HDSCT at our institution; breast
`cancer73 (51.5%), non-Hodgkin's lymphoma 30 (21%), multiple myeloma 19 (13.7%), and
`ovarian cancer 12 (8.5%), AML 2 (1.4%), CLL 2 (1.4%), Hodgkin's lymphoma I (0.96%),
`small cell lung cancer 1 (0.71 %), and testicular cancer 1 (0.71%). GT treatment was initiated
`in June of 1999. Prior to the use of GT, the prevalence of positive cultures was 67% (63
`positive cultures in 94 patients). Following the use of GT the rate of positive cultures fell
`to 47.7% in the 44 GT patients (21 positive cultures in 44 patients), a statistically significant
`difference (2-tail Fisher's Exact Test p = .0396). GT, as expected, had no effect on the prevalence
`of viral (3.2% vs. 2.3%) and fungal infections (3.2% vs. 2.3%). In these patients 21 had
`positive gram-negative cultures and sixty-two had positive gram-positive cultures. GT did
`not significantly reduce the prevalence of gram-negative strains, 17 % to 11.2 % (Fisher's
`exact test 2 tailed p = 0.455), but there was significant reduction in the prevalence of gram-
`positive strains from 60.6% to 42.2% (Fisher's exact 2 tailed p = 0.066). The hospital stay
`for group A patients was 23 days, while in group B patients it was 19.5 days (Kmskal-
`Wallis P = 0.077). Clinically, time to leukocyte engraftment was not significantly different
`between the A and B groups, 13.2 days versus 12.4 days. The median time to platelet
`engraftment for group A was 15 days and group B was 12 days(Kmskal-Wallis two tailed
`p= 0.006). Seventeen patients died within one hundred days of stem cell transplantation.
`We evaluated the effect of GT on survival to one year. There was no survival difference
`between group A and group B patients (Two tailed Log Rank p = 0.88), where 74% of the
`group A and 70% of the group B patients achieved one-year survival. Finally, the prevalence
`of non-prophylactic antibiotic therapy was unaffected by the use of GT and the median time
`on non-prophylactic antibiotics was identical between the two groups, 13 days. We conclude
`that the use of GT significantly reduced the incidence of gram-positive bacterial cultures in
`the study population as compared to those that did not receive GT. In addition, the use of
`GT is linked to a longer time to platel~t engraftment.
`
`Abstract# 5171
`The Influence of Amifostine of the Immune-Reconstitution after
`Conventional- and High-Dose Chemotherapy in Patients with
`Germ Cell Tumor. Oliver 0. Rick*, 1 Joerg J. Beyer*/ Stefan S. Serke*,3
`Nimrod N. Schwella* ,3 Wolfgang W. Siegert. 1 1 Charite Berlin, Oncology!
`Hematology, Berlin, Berlin, Germany; 2Universitaetsklinikum Marburg,
`Hematology/Oncology, Marburg, Hessen, Germany; 3Charite Berlin,
`Hematology/Oncology, Berlin, Berlin, Germany.
`We assessed the influence of amifostine on immune-reconstitution after conventional-
`dose (CDCT) and high-dose chemotherapy (HDCT) followed by autologous peripheral
`blood progenitor cell (PBPC) rescue in patients with germ cell tumor (OCT). Fourty patients
`were treated with one day cycle of 175 mg/qm paclitaxel, 5 g/qm ifosfamide (TI) plus 10 Jlg/
`kg/day granulocyte-colony stimulating factor (G-CSF) to mobilize PBPC, followed by 3
`cycles ofCDCTwith 175 mg/qm paclitaxel, 6 g/qm ifosfamide, 100 mg/qm cisplatin (TIP)
`plus 5 Jlg/kg/day G-CSF and one course of HDCT with 1,5 g/qm carboplatin, 2.4g/qm
`etoposide, 450 mg/qm thiotepa (CET) plus PBPC rescue and 5 J.Lg!kg/day 0-CSF. All
`patients were randomized to receive an absolute dose of 500 mg amifostine (group A, n= 20)
`on each day of chemotherapy or no arnifostine (group B, n= 20). Immune status was measured
`prior each cycle ofCDCT, prior HDCT, after hematologic engraftment from CET as well as 6
`
`Exh. 1046