bluuebunny/crossref_metadata_2025 huggingface dataset:
Nilotinib is associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP)
Authors: Jabbour E. , le Coutre P. , Baccarani M. , Bhalla K. , Ossenkoppele G. J. , Hochhaus A. , Gattermann N. , Haque A. , Weitzman A. , Kantarjian H.
Published: March 2020

7039

Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib and is an important therapeutic option for patients (pts) who have either imatinib-resistant or -intolerant CML disease. Results of a subset of pts with Ph+ CML-CP who received nilotinib for imatinib-intolerance are reported Methods: Pts were part of a phase II open-label study evaluating the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP. Imatinib intolerance was defined as no MCyR and discontinuation of imatinib due to Grade 3/4 AEs or persistent (> 1 mo) or recurrent Grade 2 AE (recurred > 3 times) despite optimal supportive care. The proportion of pts achieving MCyR was the primary endpoint, and safety and toxicity were secondary endpoints. Planned starting dose was nilotinib 400mg BID. Results: Of the 316 pts with CML-CP enrolled, 95 (30%) pts had imatinib-intolerance for either non-hematologic and/or hematolgic AEs. Some pts had more then one AE satisfying the criteria for intolerance. The frequency of intolerant symptoms for imatinib and nilotinib is shown in the table below. Only 2/80 (3%) pts with non-hematologic imatinib-intolerance experienced a recurrence of similar symptoms during nilotinib therapy. 33 patients entered the study due to hematologic intolerance (neutropenia, thrombocytopenia) and only 7/33 (21%) developed similar problems. In 86 pts with intolerance and at least 6 mos of follow up, 55% of these patients achieved MCyR, similar to that previously reported for imatinib-resistant patients. Conclusions: These are the first reported results evaluating cross intolerance symptoms to TKIs. The results demonstrate that nilotinib is effective in imatinib-intolerant CML-CP and has a very low rate of cross- intolerance, further supporting the excellent tolerability of nilotinib

No significant financial relationships to disclose.

[Table: see text]
A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)
Authors: Larson R. , Ottman O. , Kantarjian H. , le Coutre P. , Baccarani M. , Weitzman A. , Giles F.
Published: March 2020

7040

Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. In a phase I trial, nilotinib demonstrated efficacy and favorable tolerability in these pts. These results expand upon the phase I experience Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult imatinib-resistant or - intolerant BC pts or pts with relapsed/refractory Ph+ALL. Primary endpoint was investigator assessment of best hematologic response for BC and complete response for Ph+ALL pts. Nilotinib was started at 400mg BID with escalation to 600mg BID if no adequate response. Results: Safety and efficacy data are reported for 120 BC (27 lymphoid, 87 myeloid, 6 unknown) and 41 Ph+ALL pts (37 active disease, 4 residual disease, 38 relapsed, 3 refractory). 60% of pts had >35% Ph+ metaphases for BC and 31% for Ph+ALL. Median ages was 54 yrs for BC and 46 yrs for Ph+ALL pts. Chromosomal abnormalities other than Ph+ were noted in 64 (53%) BC and 12 (29%) Ph+ALL pts. Extramedullary involvement was present in 44 (37%) BC and 3 (7%) Ph+ALL pts. Treatment is ongoing for 21 (18%) BC and 4 (10%) Ph+ALL pts. Majority of discontinuations were due to disease progression [61 (51%) in BC; 26 (63%) in Ph+ALL). Median treatment duration was 53 (1–441) and 72 (3–363) days for BC and Ph+ALL, respectively. Median dose intensity was 800mg/day for both pt groups. CHR was reported in 25 (21%) pts, marrow responses in 7 (6%) pts, and return to chronic phase in 10 (8%) pts. Complete response was reported in 10 (24%) Ph+ALL; of which, 1 patient had minimal residual disease. The most common Grade 3/4 AEs were thrombocytopenia (41%), neutropenia (28%), pneumonia (11%), and anemia (27%) in BC and thrombocytopenia (24%) in Ph+ALL pts. During study period death occurred in 9 (8%) BC and 3 (7%) Ph+ALL pts. No Ph+ALL pt developed CNS disease while on therapy. Conclusions: Nilotinib has significant clinical activity and is well tolerated in imatinib-resistant or -intolerant BC and relapsed/refractory Ph+ALL pts. Nilotinib represents an important new treatment option for these pts in which there remains a high unmet medical need.

No significant financial relationships to disclose.
Central nervous system (CNS) leukemia after imatinib mesylate therapy for chronic myelogenous leukemia (CML)
Authors: Solh M. M. , Kantarjian H. , O'Brien S. , Giles F. , Faderl S. , Garcia-Manero G. , Rios M. , Shan J. , Cortes J. , Ravandi-Kashani F.
Published: March 2020

7042

Background: Imatinib is the standard first line treatment for CML. Imatinib penetrates the CSF poorly. We examined the incidence and outcome of CNS disease in pts with CML treated with imatinib at our institution. Methods: The clinical data for pts with early or late chronic phase and accelerated phase CML treated with imatinib between 1999 and 2006 were reviewed. Pts who were started on imatinib elsewhere and progressed to blast phase were also included. CNS disease was defined as a pathologically proven enhancing lesion (leptomeningeal or parenchymal) or presence of CSF leukemic cells. Results: Nine hundred and ten pts with chronic or accelerated phase CML were treated with imatinib. Fifty five developed blast crisis while on imatinib; another 28 pts had blast transformation while receiving imatinib elsewhere, making up a total of 83 pts. At diagnosis, their median age was 51 yrs, median Hgb, WBC and PLT counts were 10.6 g/dl, 59.7×109/L and 307×109/L, respectively. Median time from diagnosis to starting imatinib was 45.4 mts and the median duration of imatinib therapy was 17.9 mts. Fifteen pts had achieved a complete cytogenetic response and 47 had a complete hematologic response before progressing to blast phase. Their median overall survival from diagnosis was 73.2 mts. Thirty pts developed extramedullary disease; they had similar baseline characteristics as the rest with a median survival of 68.3 mts. Fifteen pts developed CNS disease (5 leptomenigeal, 5 CSF, 3 parenchymal, and 2 spinal cord); 14 had concomitant medullary blast crisis. They had a statistically significant younger age at diagnosis (41.9 vs 52.4 yrs), lower platelet counts (186 vs 334×109/L), and shorter overall survival (66.7 vs 73.2 mts) compared to the other pts with blast phase. Conclusions: CNS disease occurs infrequently in pts receiving imatinib for CML but should be suspected in pts with relevant symptoms. Pts developing CNS leukemia had a worse prognosis; this may be secondary to an inherently worse disease, poor CSF penetration of imatinib, and subsequent difficulty in eradicating CNS disease using available therapies. More potent tyrosine kinase inhibitors, such as nilotinib and dasatinib, and new agents with the ability to cross the blood-brain barrier should be evaluated in this setting.

No significant financial relationships to disclose.
Imatinib (I) plus etoposide (Vp16) compared to I + cytarabine (Ara-C) for the frontline treatment of accelerated phase (AP) chronic myeloid leukemia (CML)
Authors: Cervera E. , Vargas P. , Cruz J. , Enriquez V. , Martinez A. , Lozano V. , Candelaria M. , Labardini J. , Hurtado R.
Published: March 2020

7047

Background: Higher doses than 600 mg/day of I is the most recommended initial treatment of advanced CML disease. Nevertheless clinical and molecular results are lower than on early chronic phase, challenging for new treatment developments in face to better results. Main objective of present trial was to increase the hematological (HR) and major cytogenetical responses (MCR) with the addition of Ara- C or Vp16 to I at doses higher than 600 mg/day as a frontline therapy of AP CML. Methods: on march, 2004 we began this multicentric, phase III randomized, clinical trial, comparing I (600 mg/day) plus Vp16 (50 mg PO/day for 7 days/ 21 days cycles) vs I (600 mg/day) plus subcutaneous Ara-C (10 mg/m2/day, for 7 days/21 days cycles), doses could be adjusted due to tolerance and toxicity and in case of failure to respond at 3 months, I doses could be escalated to 800 mg/day. Inclusion criteria: newly diagnosed AP (hematological or clonal evolution permitted) CML, not elective to allogeneic transplant. Primary endpoint was the acquisition and time to acquisition of HR, MCR by conventional criteria. Secondary endpoints were main toxicities, dead to progression and overall survival. Results: 35 patients were randomized with median follow-up pf 487 days (range 21–858) for entire group. Table 1 shows results for both treatment arms. Table 1 Important toxicities (more than grade II) were thrombocytopenia (20%), neutropenia (28%) and gastrointestinal disturbances (32%) for entire group. Statistical analysis for response and toxicity (chi-square, paired T-student, Log-rank survival analysis) did not show significant differences among treatment arms. . Conclusions: We can not observe significant differences among both treatment arms, but important to note is the rates of HR and MCR, suggesting than the addition of chemotherapy could decrease the leukemic burden improving the function of I. Further research is required to confirm this data.

No significant financial relationships to disclose.

[Table: see text]
Contributions of the kinase cross-reactivity profile of MK-0457 to clinical activity
Authors: Buser C. A. , Furey B. , Hoover R. , Harding M. , Pollard J.
Published: March 2020

7050

Background: MK-0457 was designed as a small-molecule inhibitor of the Aurora kinases, AUR A, B, and C (Ki,app = 0.66–18 nM). Kinase screens indicate high selectivity of MK-0457 over other Ser/Thr kinases, but nM potency against a small set of wild type and mutant Tyr kinases, including BCR-ABL, JAK-2, and FLT-3. Consistent with this biochemical profile, MK-0457 has clinical activity in patients with chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) with the T315I BCR-ABL mutation and in patients with JAK-2 positive myeloproliferative diseases (MPD). This study compared the enzyme inhibitory profile of MK0457 with kinase inhibition profiles in cell models to further associate biological and clinical activity. Methods: MK-0457 was tested against a panel of ∼200 kinases (at Km for ATP). Viability of BaF3 cells transfected with wild type or mutant BCR-ABL or FLT3 (D845Y and FLT3-ITD mutants) was measured in MTS assays (72 hrs). Cell cycle profiles were determined by FACS analyses. Cellular inhibition of kinase activities was measured by Western Blots using phospho-substrate specific antibodies. Results: In enzyme profiling, MK-0457 (200 nM) shows = 50% inhibition of ABL, T315I ABL, ABL2, FLT-3, FLT-3 D835Y, BMX, JAK2, YES, LYN, and LCK kinases. Western blot analyses indicate nM IC50s for inhibition of phosphorylation of AUR B, Histone H3 (AUR B substrate), FLT-3, BCR-ABL, and STAT5 (substrate of BCR-ABL and FLT-3 mutants). In addition to AUR kinase inhibition, the Tyr kinases are expected to be inhibited at clinical doses of 24–32 mg/m2/hr (achieving plasma exposures of >1 μM in patients). Depsite its multi-kinase profile, MK-0457 induces similar cytotoxicity (IC50 ∼300 nM) and shows an AUR B-like inhibitory phenotype of G2/M arrest, endoreduplication and apoptosis in BaF3 cells transfected with ABL or FLT-3 (mutant and wild type) kinases. Conclusions: MK-0457 is a potent Aurora kinase inhibitor with cross-reactivity against a small set of Tyr kinases. Although MK-0457 displays an AUR inhibition phenotype in cells, inhibition of these Tyr kinases may contribute to its observed clinical activity in T315I mutant CML and ALL and in JAK-2 positive MPD.

No significant financial relationships to disclose.
Trisomy 13 in patients with hematological malignancies
Authors: Santana-Davila R. , Ellliott M. , Hook C. , Kaufmann S. , Letendre L. , Pruthi R. , Tefferi A. , Van Dyke D. , Wiktor A. , Litzow M. R.
Published: March 2020

7055

Introduction: Cytogenetic abnormalities have been shown to be the most important determinant of prognosis in patients with acute myeloid leukemia (AML). In AML, trisomy 13 has been placed in the intermediate prognostic category although recent reports associate it with a more dismal outcome. The number of cases reported in the literature are relatively few, we reviewed our experience with trisomy 13 in hematologic malignancies to determine its significance and prognosis. Methods: We conducted a clinicopathological review of cases seen in our institution from January of 1990 to October of 2006. Our cytogenetic records were searched for patients, who had a hematological disorder whose non-stimulated bone marrow karyotype was found to have trisomy 13 as a sole abnormality. In men the absence of the Y chromosome was not regarded as a separate abnormality. Results: A total of 27 patients were identified. The median age was 76 years (range 25–87), 22/27 were male. The number of cases and diseases identified were 15 with AML, 5 with a myelodysplastic syndrome, 4 with an uncategorized myelodysplastic/myeloproliferative disorder, 2 with acute lymphoblastic leukemia and 1 with a chronic myeloproliferative disorder. Of the AML group 7 were M0 according to the FAB classification, 2 patients were identified to have M4 and another two M2. A single case each of M1 and M6 was also identified. In these 15 patients, 9 underwent induction chemotherapy, which consisted of intermediate dose Ara-C in 3 cases, anthracycline plus Ara-C in 5 patients, and daunorubicin, vincristine and prednisone in 1. Another 3 patients were given palliative treatment. For the rest of the subjects the type of treatment was unknown. A CR was obtained in 6 patients, 1 patient underwent a myeloablative stem cell transplant. Death has occurred in 24 patients, the median survival of the entire group was 5.4 months. In the patients with AML the median survival was 4.7 months, of the patients who achieved a CR the median survival was 9.5 months. Conclusions: We describe one of the largest series reported to date of trisomy 13 in hematologic malignancies and found that trisomy 13 is associated with male gender and an older age at presentation, as well as a poor prognosis. In AML its presence is associated with an FAB-M0 phenotype and its occurrence should be regarded as a high-risk feature.

No significant financial relationships to disclose.
A new prognostic score for patients with lower-risk myelodysplastic syndrome (MDS) allows the identification of a subset of patients with poor prognosis
Authors: Shan J. , Kantarjian H. , Pierce S. , Estey E. , Garcia-Manero G.
Published: March 2020

7076

Background: Current prognostic models of MDS do not allow the identification of patients (pts) with lower risk disease and poor prognosis. Methods: We evaluated the characteristics of 898 pts with low or intermediate-1 disease by IPSS referred at MDACC from 1976 to 2005. Distributions of OS and progression-free-survival (PFS) were estimated by the method of Kaplan and Meier and compared between subgroups using the log rank test. Cox proportional hazards regression model was used to assess the ability of patient characteristics to predict OS and PFS, with goodness-of-fit assessed by Martingale residual plots, the Grambsch-Therneau test, Schoenfeld residual plots, and the likelihood ratio (LR) test. Multiple patient characteristics were evaluated including ferritin and β2- microglobulin, but these last two were not included in the multivariate model because their values were only known for a subset of patients.None of the patients had received chemotherapy prior to referral. Results: Median age was 66 years (range 16–94), and 65% had diploid cytogenetics. Only 88 pts (10%) transformed to AML and 388 (43%) had died. By multivariate analysis, characteristics associated with a worse OS were low platelets, anemia, older age, higher percent of marrow blasts and poor risk cytogenetics. Although not included in the model, higher ferritin (p=0.03) and β2-microglobulin (p=0.001) levels were associated with worse prognosis.These allowed the development of a scoring system in which patients could be grouped in 3 categories. Patients in category 1 (score less than 0.7) (n=22%) had a median survival of 69 months (95% CI 55-NA) and a 4-year OS of 67%, in category 2 (score 0.7–1.2) (n=40%) of 25 months (95% CI 18–31) and a 4-year survival of 28%, and in category 3 (score more than 1.2) (n=38%) of 17 months (95% CI 15–20), and a 4 -year survival of 12%. The model could segregate patients in each IPSS category (low and int-1). A subset of patients with intermediate-1 risk treated with decitabine could also be stratified by the model. Conclusions: This data indicates that it is possible to identify patients with lower-risk MDS and poor prognosis that may benefit from early therapeutic intervention.

No significant financial relationships to disclose.
Tolerability and hematologic improvement assessed using three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes
Authors: Lyons R. M. , Cosgriff T. , Modi S. , McIntyre H. , Beach C. L. , Backstrom J. T.
Published: March 2020

7083

Background: At a dosing schedule of 75 mg/m2/day SC for 7 days every 4 weeks, azacitidine is an effective and safe treatment (Tx) for patients (pts) with myelodysplastic syndromes (MDS) (JCO 2002; 20:2429). An alternative dosing schedule that eliminates the need for weekend dosing would be more convenient to pts and clinicians. Methods: In this phase II, multicenter, open-label trial, pts with MDS were randomized to 1 of 3 regimens that were repeated every 4 weeks: AZA 5–2-2 (75 mg/m2/day × 5 days, followed by 2 days no Tx, followed by 75 mg/m2/day × 2 days), AZA 5–2-5 (50 mg/m2/day × 5 days, followed by 2 days no Tx, followed by 50 mg/m2/day × 5 days) or AZA 5 (75 mg/m2/day × 5 days). To determine if response/improvement according to International Working Group criteria (Blood 2000; 96:3671) can be maintained after 6 cycles, the study was amended to include a 12-month maintenance comparing AZA 5 every 4 weeks with AZA 5 every 6 weeks. Results: As of Nov. 30, 2006, 138 pts have been randomized to AZA 5–2-2 (n=46), AZA 5–2-5 (n=47) and AZA 5 (n=45). Most pts are RA (43%) or RAEB (30%), based on FAB classification. Of 104 pts who have received =2 cycles of Tx, hematologic improvement (major or minor in at least 1 cell line) occurred in 63% (65) of the patients ( Table ). Of these pts, 14% had a bi-lineage (AZA 5–2-2: 11%, AZA 5–2-5: 10%, AZA 5: 22%) and 6% had a tri-lineage AZA 5–2-2: 6%, AZA 5–2-5: 7%, AZA 5: 5%) response (based on any improvement). Ongoing pts in the study include AZA 5–2-2: 41% (19/46), AZA 5–2-5: 47% (22/47), and AZA 5: 58% (26/45). No treatment-related mortality has been reported. Most Tx-related grade 3 or 4 events were hematological (AZA 5–2-2: 39%, AZA 5–2-5: 24%, AZA 5: 16%). Updated data, including several pts who have completed at least 6 cycles maintenance, will be available at the time of the meeting. Conclusions: These data indicate that the 3 alternative azacitidine dosing schedules are safe, effective, and similar in efficacy with the FDA-approved regimen.

[Table: see text] [Table: see text]
Evaluation of risk for development of myeloproliferative disorders, myelodysplastic syndromes, or acute leukemias with long-term eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients
Authors: Schubert J. , Young N. S. , Luzzatto L. , Brodsky R. A. , Socié G. , Rother R. P. , Rollins S. A. , Hillmen P.
Published: March 2020

7087

Background: PNH is a rare bone marrow failure disorder defined by stem cell clones with somatic mutations in the PIG-A gene. These mutations result in peripheral blood cells deficient in GPI-anchored proteins including complement inhibitors CD55 and CD59. Chronic lysis of PNH RBCs leads to severe anemia, life-threatening thrombosis, debilitating fatigue, and impaired quality of life. Previous studies have indicated an increased frequency of myeloproliferative disorders, MDS, and acute leukemias in PNH. In a previous retrospective analysis of 1,760 PNH patients, 6.8% developed either myeloid or lymphoid disorders and 1% developed acute leukemias. Eculizumab (Soliris) is a humanized antibody that prevents terminal complement activation. Long-term eculizumab treatment has been evaluated in 195 PNH patients (>250 patient years of exposure) and shown to significantly restore the endogenous PNH RBC clone resulting in improved anemia, as well as significant improvements in thrombosis, fatigue, and quality of life. Methods: Leukocyte clone sizes were assessed at baseline and 26 weeks for patients receiving eculizumab in the Phase III clinical trials (TRIUMPH and SHEPHERD) using flow cytometry. The frequency of MDS and leukemia was calculated as a percentage of the eculizumab-treated patients across all eculizumab trials. Results: PNH leukocyte clone size did not increase with eculizumab treatment (median 96.1% at baseline vs 95.5% at week 26; P=0.80, signed rank test) suggesting that inhibition of terminal complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the frequency of new MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The single case of CMML occurred in a patient previously diagnosed with and was attributed to high grade myelodysplasia. Conclusions: To date, eculizumab treatment of PNH patients does not increase the risk for the development of myeloproliferative disorders, MDS or acute leukemias. Patients on eculizumab will continue to be followed in a Global PNH Safety Registry.

No significant financial relationships to disclose.
Improved risk assessment in B-cell chronic lymphocytic leukemia based on sex-specific molecular profiling
Authors: Tinhofer I. , Rubenzer G. , Holler C. , Stoecher M. , Egle A. , Greil R.
Published: March 2020

7090

Background: B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with some patients having an indolent course and others a rapidly progressing one. As underlying molecular mechanisms of differential disease activity, genomic aberrations, the mutational status of the variable region of the immunoglobulin heavy chain (Ig VH) and distinct expression levels of Zap-70 and CD38 have recently been identified, and their capacity to interact with survival and proliferation signals of B-CLL cells has directly been linked to progression and response to therapy. Although male sex has also been identified as risk factor for a more aggressive disease in B-CLL, the molecular basis for this interaction remains elusive. Methods: We compared the prognostic value of the above-mentioned molecular risk factors between female (n=88) and male patients with B-CLL (n=116). Differences in their frequency was evaluated using the Chi-square test. Their impact on treatment-free and overall survival of patients was analyzed using the Kaplan-Meier method and the log-rank test. The prognostic value of each molecular risk parameter in female and male patients was determined using the Cox proportional hazards regression model. Results: High CD38 expression (=30%), unmutated Ig VH gene (=98%) and unfavorable genetic aberrations (i.e. del17p, del11q or tri12) detected in the neoplastic clone identified patients with significantly shortened treatment-free survival, irrespective of the sex of patients. In contrast, Zap70 expression in more than 20% of B-CLL cells was negatively associated with treatment-free survival only in female (RR: 3.5, 95% CI 1.5 –7.9, P=.003) but not in male patients (RR: 1.6, 95% CI 0.9 –2.9, P=.089). In addition, we identified high CD38 expression in T-cells as independent negative prognostic marker in male (RR: 2.8, 95% CI 1.5 –5.0, P=.0006) but not in female patients (RR: 1.9, 95% CI 0.8 –4.6, P=.17). Based on these results we developed a novel sex-adapted algorithm for improved risk assessment in B-CLL. Conclusions: We identified sex-specific differences in the prognostic value of Zap-70 and CD38 in B-CLL. Whether this can be explained by modulation of their specific signaling pathways by sex hormones will have to be addressed in future studies.

No significant financial relationships to disclose.
Assessment of the hematopoietic cell transplantation comorbidity index in non-Hodgkin lymphoma patients receiving reduced intensity allogeneic hematopoietic cell transplantation
Authors: Pollack S. , Steinberg S. , Odom J. , Dean R. , Fowler D. , Bishop M. R.
Published: March 2020

7096

Background: Several patient-related factors influence outcomes after allogeneic hematopoietic cell transplantation (HCT). The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), a weighted index of 17 pre-transplant comorbidities, has been validated in non- myeloablative HCT studies, but it has not been tested in non-Hodgkin's lymphoma (NHL) patients receiving reduced-intensity conditioning (RIC) HCT nor has it been compared with a number of other pre-transplant factors. Methods: We performed an analysis of 63 NHL patients treated with RIC HCT to assess the HCT-CI's impact on overall survival (OS), treatment-related mortality (TRM) and disease-related mortality (DRM). Individual factors, including performance status, single comorbidities, CD34 dose, prior chemotherapy number, pre-transplant induction chemotherapy response, and NHL histology, were also analyzed relative to their impact on OS. Prior to transplant, all patients received an identical induction regimen (EPOCH-fludarabine). All patients received identical RIC (Cy/Flu) and were transplanted from HLA-matched siblings. Results: In univariate analysis, each of the above factors, except for histology and CD34 dose, exhibited a trend toward an association with OS (adjusted p<0.10). The HCT-CI (0–2 comorbidities vs. 3+ comorbidities) demonstrated an association with TRM at 100 days (4.5% vs. 26.3%) and 1 year (13.6% vs. 36.8%) post-transplant, but not DRM. The factor most strongly associated with OS was response to induction chemotherapy (CR/PR/SD vs. PD; p=0.0025). In a Cox model for OS, induction chemotherapy response remained the sole important factor, while the HCT-CI and other pre-transplant factors added little predictive value to the induction chemotherapy response. The HCT-CI was more strongly associated with OS and TRM in a subset analysis restricted to patients in CR/PR following induction chemotherapy. Conclusions: These findings suggest that the HCT-CI may be useful for estimating probabilities of TRM and OS in NHL patients being considered for RIC HCT. The data further suggest that chemotherapy response at transplant may have significant impact on transplant outcomes.

No significant financial relationships to disclose.
Phase II non-randomized trial using pegfilgrastim for hematopoietic recovery after autologous peripheral stem cell transplantation
Authors: Patel S. A. , Sethi S. , Holter J. , Selby G.
Published: March 2020

7101

Background: Filgrastim (FIL), granulocyte-colony stimulating factor(G-CSF) reduces time to neutrophil engraftment, hospital stay and antibiotic therapy but requires uncomfortable and inconvenient daily subcutaneous (SC) injections.Pegfilgrastim (PFIL), while more expensive, requires a single SC injection.Before changing our practice and for internal validation, we initiated phase II nonrandomized trial using PFIL instead of FIL for hematopoietic recovery after autologous peripheral stem cell transplantation(autoPBSCT).An interim analysis of this study was presented (Poster No: - 417) at 2006 BMT Tandem Meetings.Here we present a complete analysis of our study. Method: A Phase II nonrandomized trial compares a single injection PFIL 6mg SC on Day +1 to historical controls using FIL 5mcg/kg SC daily starting Day+7 and continued until ANC=500/mm3 for three consecutive days.Twenty-two patients prospectively(05/2005–06/2006) accrued (MM=2; NHL=13; HD=7, MM=Multiple Myeloma, NHL= Nonhodgkin's lymphoma, HD= Hodgkin's lymphoma).Sixty-six consecutive patients retrospectively (MM=21; NHL=25; HD=20) were analyzed as historical controls(04/1999–04/2005).This study has been completed and closed. The primary endpoint of this study was to determine the days needed to engraft neutrophils & platelet following PFIL administration after autoPBSCT. Wilcoxon Rank Sums test performed for all comparisons except gender comparison was done by chi-square test. Results: Use of a single convenient injection of PFIL resulted in earlier neutrophilic recovery, less packed red blood cell(PRBC) transfusion & shorter hospital stay. No PFIL patients required additional G-CSF. One patient had prolonged fever probably PFIL- related. Conclusion: Our phase II study indicates the equivalency of PFIL and FIL related to hematopoietic recovery after autoPBSCT.

No significant financial relationships to disclose.

[Table: see text]
Outpatient autologous stem cell transplants for selected patients with myeloma: Morbidity, mortality, and duration of hospitalization
Authors: Liu S. , Vogl D. T. , Chong E. A. , Luger S. M. , Porter D. L. , Schuster S. J. , Tsai D. E. , Andreadis C. , Nasta S. D. , Mangan P. A. , Stadtmauer E. A.
Published: March 2020

7104

Background: High-dose melphalan with autologous stem cell support improves survival for patients with myeloma but often requires prolonged inpatient hospitalization. Short hospitalization with close follow-up may reduce complications, cost, and duration of total hospitalization for selected patients with good performance status and social support. Methods: We reviewed all initial autologous transplants for myeloma from 1/03–4/06, categorized by length of initial hospitalization as brief stay (≤4 days) or prolonged stay (≥5 days). Clinical selection for a brief stay had been based on a combination of age; cardiac, pulmonary, and renal function; performance status; availability of caregivers at home; distance from our medical center; and patient preference. We reviewed the post-transplant course to 100 days and calculated cumulative hospitalization by adding length of initial hospitalization to that of subsequent readmissions within 100 days. Results: 148 patients received an initial transplant for myeloma: 64 were selected for brief stay and 84 for prolonged stay. There were no significant differences in age or in renal function, Durie-Salmon stage, or B2-microglobulin at diagnosis. Brief stay patients were discharged home after stem cell reinfusion, with first follow-up scheduled 3–14 days later. Care at home included a nurse visit after discharge, intravenous fluids and ondansetron, and oral antibiotics, with blood work twice weekly. 46% of brief stay patients required readmission during the first 100 days and had a median of 8.5 cumulative hospital days post-transplant, as compared to 18 days for prolonged stay patients (p=0.0001). There were fewer documented infections among brief stay patients (29.7% vs 50.0%, p=0.01) and fewer admissions to intensive care units (0 vs 6.0%, p=0.047). The groups had similar rates of bleeding (1.6% vs 4.8%, p=0.3) and thrombosis (3.1% vs 8.3%, p=0.2). No patients in the brief stay group died within 100 days, while mortality in the prolonged stay group was 4.8% (p=0.08). Conclusion: Selected patients receiving an autologous stem cell transplant for treatment of myeloma can be managed with brief initial hospitalization and outpatient follow-up, with low morbidity and mortality.

No significant financial relationships to disclose.
Monitoring plasma voriconazole levels may prevent subtheraputic dosing in pediatric stem cell transplant (SCT) patients
Authors: Morris J. D. , Voskoboynik D. , Brown W. C. , Czarnecki S. , Morris C. L.
Published: March 2020

7105

Background: Voriconazole is frequently used for prophylaxis and treatment of fungal infections during hematopoeitic stem cell transplant (SCT). Clinical studies demonstrate a poorer outcome when voriconazole concentrations are ≤0.5mcg/ml. Pediatric dosing schedules to achieve trough concentrations >0.5mcg/ml are not established. Methods: Retrospective analysis of voriconazole levels in 16 pediatric allogeneic SCT patients recieving fungal prophylaxis with oral or iv voriconazole. Ages ranged from 0.5 to 16 years, median 8 years. Serum levels were measured by high-performance liquid chromatography. Samples were obtained 5 to 7 days after start or change of voriconazole therapy. Ninety-eight total levels were evaluated. Results: Eight patients (50%) achieved a trough level > 0.5mcg/ml on the majority of samples tested at doses ranging from 3.5 to 10 mg/kg po q 12 hours. At constant dose there was a significant intra-patient variability in trough levels over time. Most patients failing to achieve adequate trough levels were below the median age (see table ). Changing to iv therapy in 3 patients with low trough levels after oral therapy did not improve the trough levels. Multi-time point measurements were > 0.5mcg/ml at 2 to 6 hours after oral dose, but fell to < 0.2mcg/ml by 12 hours in 3 patients tested. Of 98 voriconazole levels, 52 were ≤ 0.5mcg/ml and 74 were < 1.0 mcg/ml. Conclusions: Unlike reports in adult patients, we found that frequent monitoring of voriconazole levels was necessary in pediatric SCT patients due to intra-patient variability. Younger pediatric SCT patients may require more frequent dosing schedules to achieve trough levels.

No significant financial relationships to disclose.

[Table: see text]
Autologous hematopoietic stem cell transplantation with a rituximab-containing preparative regimen for non-Hodgkin lymphoma
Authors: Kamble R. T. , May R. , Ganguly S. , Heslop H. E. , Brenner M. K. , Carrum G.
Published: March 2020

7112

Background: We investigated the safety and outcome after adding Rituximab to our standard high-dose chemotherapy conditioning regimen with BEAM in patients receiving autologous hematopoietic stem cell transplantation. Methods: Between November 2002 and May 2006, 25 consecutive patients with relapsed high-risk NHL (diffuse large B cell = 15, transformed follicular =10) were enrolled. The high-dose chemotherapy regimen consisted of BEAM with rituximab administered at 375 mg/m2 IV on days −6, +14, +21 and +28. Rituximab associated delayed neutropenia was defined as ANC of < 500 occurring at least 4 weeks after the last dose of rituximab. B cell and T cell reconstitution data was measured using phenotypic analysis for CD3, CD4, CD8, CD56, CD19 and CD20. Results: The median age was 55 years (range 22–69 years). The disease status at transplant included advanced disease (≥CR-2) in 15 while 10 had primary refractory disease. The previous initial and or salvage chemotherapy included Rituximab in all 25 patients. A median of 4.47 ×10 6/kg CD 34 + cells were infused resulting in neutrophil and platelet engraftment at 11 (10–23) and 21 (14–56) days respectively. The median time to T cell reconstitution (CD3 >1,000/uL) was 32 days, B cell recovery was delayed beyond 1 year with median of 72 CD19+ve cells/uL at 1 year. 24 (96%) patients achieved complete remission after transplant and 1 had a partial response. There was no transplant related mortality. Nine patients relapsed at a median of 4 months (2–23 months). 6 patients died at a median of 15 months from transplant (relapsed lymphoma =4 and secondary MDS=2). At a median follow-up of 24 months, the disease free survival and overall survival is 52% and 75% respectively. Rituximab associated delayed neutropenia occurred in 3 (12%) patients at a median of 39 (31–64) days from the last dose of rituximab and resolved at a median of 14 days (7–38) with or without filgrastim support. There were no infectious complications associated with neutropenia or delayed B cell recovery. Conclusion: Incorporation of rituximab into a high dose chemotherapy conditioning regimen is safe. Delayed B cell reconstitution and Rituximab associated delayed neutropenia are common but not associated with significant infectious complications.

No significant financial relationships to disclose.
Molecular analysis-directed individualized therapy (MADeIT) in advanced non-small cell lung cancer (NSCLC)
Authors: Simon G. R. , Williams C. C. , Chiappori A. A. , Haura E. B. , Tanvetyanon T. , Antonia S. J. , Bepler G.
Published: March 2020

7502

Background: RRM1 (R1) is a crucial gene for nucleotide metabolism, and it is the dominant molecular determinant of gemcitabine efficacy. ERCC1 (E1), a component of the nucleotide excision repair complex, is important for platinum-induced DNA adduct repair. We hypothesized that selection of dual agent chemotherapy based on tumoral R1 and E1 expression would be feasible and beneficial for patients with advanced NSCLC. Methods: A prospective phase II clinical trial in patients with advanced NSCLC was conducted. Patients were required to have a dedicated tumor biopsy for determination of R1 and E1 gene expression by real-time quantitative RT-PCR. The primers and probes had been validated by sequencing of cDNA amplicons. Dual agent chemotherapy consisting of carboplatin (C), gemcitabine (G), docetaxel (D), and vinorelbine (V) was selected based on gene expression as follows: GC for low R1/low E1; GD for low R1/high E1; DC for high R1/low E1; and DV for high R1/high E1. Eligibility included pathologically confirmed advanced NSCLC (stage IV and wet IIIB); PS 0–1; no prior systemic therapy for NSCLC; age ≥18; adequate hematologic, hepatic, and renal function; and measurable or evaluable disease by RECIST. Disease response and patient survival were measured. Results: Sixty eligible patients were enrolled from 2/04 to 12/05. Tumor specimens were collected in all with one minor and clinically insignificant complication. Expression analysis was successful in 55 patients. R1 expression ranged from 0–1,637; E1 expression ranged from 1–8,103; and their expression was correlated (Spearman's rho=0.46, p<0.01). The partial response rate was 44% (95% CI 31–59%). OS and PFS and were 59% and 14% at 12 months with medians of 13.3 and 6.6 months respectively. Conclusion: Therapeutic decision making based on RRM1 and ERCC1 gene expression for patients with advanced NSCLC is feasible and promising for improvement in patient outcome.

No significant financial relationships to disclose.
Randomized phase II study of maintenance vandetanib (ZD6474) in small cell lung cancer (SCLC) patients who have a complete or partial response to induction therapy: NCIC CTG BR.20
Authors: Arnold A. M. , Smylie M. , Ding K. , Ung Y. , Findlay B. , Lee C. W. , Djurfeldt M. , Seymour L. , Langmuir P. , Shepherd F.
Published: March 2020

7522

Background: Vandetanib (V) is an inhibitor of vascular endothelial and epidermal growth factor receptors. This trial sought to determine whether maintenance V, given after standard chemotherapy (CT) and radiation (RT), prolonged progression-free survival (PFS) in responding patients with SCLC. Secondary endpoints: overall survival (OS) and toxicity. Methods: Phase II randomized, study of V 300 mg PO daily or placebo (P). Eligibility: complete (CR) or partial response (PR) to platinum-based CT, ECOG PS 0–2 and completion of RT (thoracic or prophylactic cranial). Statistics: 80% power to detect a 2.5 months improvement in median PFS (estimate for P of 4 months) using a 1-sided 10% level test (100 eligible patients; 77 events). Results: Between May 2003 and March 2006, 107 patients were accrued from 17 centres. Median follow up: 13.5 months. 46 had limited disease (LD); 61 extensive disease (ED). There were fewer PS 0 patients (11 vs. 20), and fewer had CR to initial CT (4 vs. 8) in the V arm. V patients were more likely to experience toxicity and require dose modification. The most frequent toxicities leading to dose modifications were gastrointestinal and rash. Clinically asymptomatic QTc prolongation was observed in 8 V patients. 83 of 107 patients developed progressive disease (43 on V; 40 on P). The median PFS for V was 2.7 months (80% C.I.: 1.1 –4.5) and 2.8 months for P (80% C.I.: 1.9 –5.6); estimated hazard ratio (HR) was 1.01 for V vs P (80% C.I.: 0.75 –1.36, 1-sided P-value = 0.51). Median OS for V was 10.6 months vs. 11.9 months for P; HR was 1.43 for V vs. P (80% C.I.: 1.00 –2.05, 1-sided P-value = 0.90). In a planned subgroup analysis, a significant interaction was noted (P-value = 0.01); with LD patients randomized to V having a longer OS (HR: 0.45, 1-sided P-value = 0.07), whereas ED patients randomized to V had a shorter OS compared to P (HR: 2.27, 1-sided P-value = 0.996). Conclusion: V failed to demonstrate efficacy as maintenance therapy for SCLC. Future targeted therapies should probably be explored concurrently with chemotherapy. This study was supported by the Canadian Cancer Society and AstraZeneca.

[Table: see text]
Randomized, phase III study of mitomycin/vindesine/cisplatin (MVP) versus weekly irinotecan/carboplatin (IC) or weekly paclitaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (NSCLC)
Authors: Kimura T. , Uejima H. , Satouchi M. , Nakagawa K. , Hida T. , Kawahara M. , Sugiura T. , Kashii T. , Tamura K. , Fukuoka M.
Published: March 2020

7530

Background: Concurrent chemoradiotherapy plays an important role in the treatment of unresectable stage III NSCLC. Our group demonstrated a superiority of MVP with concurrent TRT over that with sequential TRT (Furuse, JCO, 1999), while weekly chemotherapy with concurrent TRT has acceptable toxicities and expected efficacy. We conducted a randomized phase III trial to compare the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP by a non-inferiority design. Methods: Patients were assigned to 3 regimens; MVP: cisplatin (80 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36) and mitomycin (8 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). After then, pts received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2) / carboplatin(AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan(50 mg/m2) / carboplatin(AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2) / carboplatin (AUC 5). Primary endpoint was overall survival. Results: From Sep 2001 to Sep 2005, 456 pts were randomized; 429 pts had evaluated responses. Pretreatment characteristics were well-balanced between 3 arms (median age 63 years (30–74), PS0/1 41/55%, Ad/Sq/others 43/45/12%). The achievement rates of full treatment in MVP, IC and PC were 39.9, 29.7, and 49.3 %; those of full-dose TRT/2 courses of consolidation chemotherapy were 81.1/41.3%, 41.4/29.7% and 59.7/50.0%, respectively. Major toxicities were as follows; G4 neutropenia in MVP, IC, PC were 76.9, 13.1, 4.2% (p<0.001), and G3–4 non-hematological toxicities (decrease in PS, and febrile neutropenia) were 13.3, 6.2, 4.2% (p=0.01), and 29.4, 6.9, 4.9% (p<0.001), respectively. The overall response rates were 65.7% (95% CI 57.9–73.5), 58.6 % (95% CI 50.5–66.1) and 62.9% (95% CI 55.0–70.8), in MVP, IC and PC, respectively. Complete analysis will be fixed in Oct 2008. Conclusions: Weekly PC with TRT appears good compliance with high achievement rate and MVP appears poor compliance with severe hematological and non-hematological toxicities.

No significant financial relationships to disclose.
A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (pts) with stage III A/B non-small cell lung cancer (NSCLC): An interim report of the RTOG 0324 trial
Authors: Blumenschein G. , Moughan J. , Curran W. , Robert F. , Fossella F. , Werner-Wasik M. , Doescher P. , Choy H. , Komaki R.
Published: March 2020

7531

Background: Cetuximab (C225) is a chimerized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). NSCLC commonly expresses the EGFR, which is associated with aggressive tumor behavior and poor clinical outcome. Preclinical model systems demonstrate radiosensitization following molecular inhibition of EGFR signaling. Methods: We report a phase II trial testing the combination of C225 with CRT in unresectable stage III NSCLC with a planned sample size of 84 PTS. Eligibility criteria included Zubrod performance status (PS) = 1, weight loss = 5% over past 3 months, FEV1 = 1.2 l, adequate hematologic, hepatic, and renal function. PTS received an initial dose of C225 (400 mg/m2) on day 1 of week 1, then weekly doses of C225 (250 mg/m2) until completion of therapy (weeks 2 –17). During week 2, patients started CRT (63 Gy/35 fractions) with weekly carboplatin (C) AUC 2 and paclitaxel (P) 45 mg/m2 × 6 doses followed by C (AUC 6) and P (200 mg/m2) × 2 cycles (weeks 12–17). Interim monitoring for severe (grade = 3) or excessive non-hematologic toxicities occurred after pts had been treated and followed for at least 90 days after RT. Primary endpoints include safety and compliance of concurrent C225 and CRT. Results: 93 pts were enrolled with 87 evaluable pts. Pts characteristics: 57% male, median age 64 years (range 42–85), 47% PS 0, 46% stage IIIA. Median follow-up is 14 months. Response rate is 62% (n=54) and 12 month overall survival (OS) is 68% (# at risk=56). Adverse events related to treatment include 20% (n=17) of pts with grade 4 hematologic toxicities and 7 pts who had grade 3 esophagitis. There was 1 infection related death, 1 death NOS, and 3 pts who died of pulmonary complications (adult respiratory distress syndrome, pneumonitis, and hypoxia). Conclusions: The combination of C225 with CRT is feasible. Further study will be needed to determine whether the addition C225 to CRT enhances toxicity or efficacy. Complete compliance and toxicity data along with 18 month OS will be reported.

No significant financial relationships to disclose.