Progressive multifocal leukoencephalopathy associated with a lymphoproliferative disorder treated with pembrolizumab.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease affecting the central nervous system as a result of reactivation of the John Cunningham (JC) polyomavirus and occurs almost exclusively in immunosuppressed individuals. The disease course of PML is variable but usually progressive and often fatal. Treatment is predominantly focused on immune restoration, although this is difficult to do outside of human immunodeficiency virus-associated PML. A recent case series demonstrated a potential role for programmed cell death protein 1 (PD-1) inhibitors, such as pembrolizumab, to contain and/or clear JC virus. Herein, we discuss the first reported Australian case of a 61-year-old female with PML secondary to chemoimmunotherapy demonstrating complete clearance of JC virus as well as clinical and radiological stabilisation following pembrolizumab treatment.

Outpatient rituximab, ifosfamide, etoposide (R-IE) in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation.

Patients with relapsed-refractory diffuse large B-cell lymphoma (RR-DLBCL) ineligible for autologous stem cell transplantation (autoSCT) have poor survival. Thirty transplant-ineligible patients older than 60 years were administered rituximab 375 mg/m2 day 1, ifosfamide 1333 mg/m2 days 1 to 3, and etoposide 80 mg/m2 days 1 to 3 (R-IE) every 21 days for 6 cycles plus 2 doses of rituximab. Revised international prognostic index 3-4 was seen in 53% and prior rituximab exposure in 60%. The complete and overall response rates were 55% and 76%, respectively. Median progression free survival (PFS) and overall survival were 23 and 24 months, respectively. Patients relapsing within 12 months of prior treatment had a median PFS of 2.5 months compared to 23 months for those relapsing beyond 12 months. Grade 3-4 thrombocytopenia and neutropenia occurred in one and eight patients, respectively. R-IE is an effective, well tolerated regimen in RR-DLBCL patients not fit for autoSCT.

Quality of life is maintained with ixazomib maintenance in post-transplant newly diagnosed multiple myeloma: The TOURMALINE-MM3 trial.

OBJECTIVES: Health-related quality of life (HRQoL) is particularly important during maintenance therapy (MT) in newly diagnosed multiple myeloma post-transplant, when disease symptoms are limited. METHODS: We assessed HRQoL in patients randomised to 26 cycles of MT (ixazomib vs placebo) in TOURMALINE-MM3 (NCT02181413). RESULTS: The characteristics at study entry were well-balanced between ixazomib (n = 386) and placebo (n = 251) arms. At study entry, EORTC QLQ-C30 and MY20 scores were high for functional scales and low for symptom scales and were comparable with those of the general population. Changes in subscale scores across intervals, analysed over 30 four-week intervals using a linear mixed-effects model, were generally small and similar between arms for the EORTC QLQ-C30 Global Health Status/QoL, Physical Functioning, and Pain subscales and EORTC QLQ-MY20 Disease Symptoms subscale and Peripheral Neuropathy item. EORTC QLQ-C30 Nausea/Vomiting and Diarrhoea subscales were consistently worse for ixazomib than for placebo, in line with the ixazomib toxicity profile. Even when least-squares mean differences between arms were statistically significant, none reached the established minimal important clinical difference of 10 in multiple myeloma. CONCLUSIONS: In addition to improvement in progression-free survival with ixazomib, HRQoL was maintained in both arms. Active treatment with ixazomib did not have an adverse impact on HRQoL.

Clinical use of SNP-microarrays for the detection of genome-wide changes in haematological malignancies.

Single nucleotide polymorphism (SNP) microarrays are commonly used for the clinical investigation of constitutional genomic disorders; however, their adoption for investigating somatic changes is being recognised. With increasing importance being placed on defining the cancer genome, a shift in technology is imperative at a clinical level. Microarray platforms have the potential to become frontline testing, replacing or complementing standard investigations such as FISH or karyotype. This 'molecular karyotype approach' exemplified by SNP-microarrays has distinct advantages in the investigation of several haematological malignancies. A growing body of literature, including guidelines, has shown support for the use of SNP-microarrays in the clinical laboratory to aid in a more accurate definition of the cancer genome. Understanding the benefits of this technology along with discussing the barriers to its implementation is necessary for the development and incorporation of SNP-microarrays in a clinical laboratory for the investigation of haematological malignancies.

Detection of complex genomic signatures associated with risk in plasma cell disorders.

Plasma cell disorders (PCD) range from benign to highly malignant disease. The ability to detect risk-stratifying aberrations based on cytogenetic and molecular genetic assays plays an increasing role in therapeutic decision making. In this study, 58 patients were chosen for screening by comparative genomic hybridisation microarray (aCGH) to identify the new high-risk prognostic markers of chromothripsis and chromoanasynthesis. All patients had an unequivocal clinical diagnosis of a plasma cell disorder (plasma cell myeloma (PCM)(n = 51) or monoclonal gammopathy of undetermined significance (MGUS)(n = 7)) and an abnormal FISH result. There were a total of 17 complex genomic events identified across 9 patient samples, which were selected for further investigation by high definition single nucleotide polymorphism (HD-SNP) microarray. Each event was analysed and characterised for chromothripsis, chromoanasynthesis or a complex step-wise chromosomal event. We describe an effective method to identify the new high-risk prognostic markers of chromothripsis and chromoanasynthesis in plasma cell disorders.

Evaluation of cardiovascular ischemic event rates in dasatinib-treated patients using standardized incidence ratios.

With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY). Overall, 2-4% of dasatinib-treated patients had cardiovascular ischemic events. Most dasatinib-treated patients with an event had a history of and/or risk factor for atherosclerosis (pooled 77 with history/risk and event/96 with events; DASISION 8/10; READY 15/18). Most cardiovascular ischemic events occurred within 1 year of initiating dasatinib (pooled 69/96; DASISION 7/10; READY 16/18). Comparison of observed and expected event rates through standardized incidence ratios indicates that dasatinib does not increase risk for cardiovascular ischemic events compared with external reference populations.

Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia.

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia.

Treatment of acute myeloid leukaemia (AML) is challenging and emerging treatment options include protein phosphatase 2A (PP2A) activators. Fingolimod is a known PP2A activator that inhibits multiple signalling pathways and has been used extensively in patients with multiple sclerosis and other indications. The initial positive results of PP2A activators in vitro and mouse models of AML are promising; however, its safety for use in AML has not been assessed. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A literature review was carried out to assess safety before the commencement of Phase I trials of the PP2A activator Fingolimod in AML. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A systematic review of published literature in Medline, EMBASE and the Cochrane Library of critical reviews was carried out. International standards for the design and reporting of search strategies were followed. Search terms and medical subject headings used in trials involving PP2A activators as well as a specific search were performed for 'adverse events', 'serious adverse events', 'delays in treatment', ' side effects' and 'toxicity' for primary objectives. Database searches were limited to papers published in the last 12 years and available in English. The search yielded 677 articles. A total of 69 journal articles were identified as relevant and included 30 clinical trials, 24 review articles and 15 case reports. The most frequently reported adverse events were nausea, diarrhoea, fatigue, back pain, influenza viral infections, nasopharyngitis and bronchitis. Specific safety concerns include monitoring of the heart rate and conduction at commencement of treatment as cardiotoxicity has been reported. There is little evidence to suggest specific bone marrow toxicity. Lymophopenia is a desired effect in the management of multiple sclerosis, but may have implications in patients with acute leukaemia as it may potentially increase susceptibility to viral infections such as influenza. Fingolimod is a potential treatment option for AML with an acceptable risk to benefit ratio, given its lack of bone marrow toxicity and the relatively low rate of serious side effects. As most patients with AML are elderly, specific monitoring for cardiac toxicity as well as infection would be required.

Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions.

Bone marrow (BM) is the preferred graft source for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) compared with mobilized peripheral blood stem cells (PBSCs). We hypothesized that this recommendation may not apply to those regions where patients present later in their disease course, with heavier transfusion load and with higher graft failure rates. Patients with SAA who received HSCT from an HLA-matched sibling donor from 1995 to 2009 and reported to the Center for International Blood and Marrow Transplant Research or the Japan Society for Hematopoietic Cell Transplantation were analyzed. The study population was categorized by gross national income per capita and region/countries into 4 groups. Groups analyzed were high-income countries (HIC), which were further divided into United States-Canada (n = 486) and other HIC (n = 1264); upper middle income (UMIC) (n = 482); and combined lower-middle, low-income countries (LM-LIC) (n = 142). In multivariate analysis, overall survival (OS) was highest with BM as graft source in HIC compared with PBSCs in all countries or BM in UMIC or LM-LIC (P < .001). There was no significant difference in OS between BM and PBSCs in UMIC (P = .32) or LM-LIC (P = .23). In LM-LIC the 28-day neutrophil engraftment was higher with PBSCs compared with BM (97% versus 77%, P = .002). Chronic graft-versus-host disease was significantly higher with PBSCs in all groups. Whereas BM should definitely be the preferred graft source for HLA-matched sibling HSCT in SAA, PBSCs may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infective complications.

To adhere or not to adhere: Rates and reasons of medication adherence in hematological cancer patients.

To conduct a comprehensive review to examine among hematological cancer patients: (1) rates of adherence to self-administered cancer treatments; and (2) factors impacting on their adherence. Fifty two eligible publications were identified. The majority focused on Chronic Myeloid Leukaemia (CML) (n=40) and Acute Lymphoid Leukaemia (ALL) (n=11) patients. Adherence rates varied and depended on the definition and measures used. Patient understanding about their disease and treatment, and forgetting to take their medication impacted on patients' level of adherence; while the use of reminders reduced forgetfulness. There is a lack of valid and reliable information relating to medication adherence of hematological cancer patients. Based on the limited data available we provide a profile of CML and ALL patients at potential risk of medication non-adherence, as well as a proposed checklist that can be used by health care providers in assessing and supporting patients in adhering to their medication.

A longitudinal evaluation of performance of automated BCR-ABL1 quantitation using cartridge-based detection system.

An automated cartridge-based detection system (GeneXpert; Cepheid) is being widely adopted in low throughput laboratories for monitoring BCR-ABL1 transcript in chronic myelogenous leukaemia. This Australian study evaluated the longitudinal performance specific characteristics of the automated system.The automated cartridge-based system was compared prospectively with the manual qRT-PCR-based reference method at SA Pathology, Adelaide, over a period of 2.5 years. A conversion factor determination was followed by four re-validations. Peripheral blood samples (n = 129) with international scale (IS) values within detectable range were selected for assessment. The mean bias, proportion of results within specified fold difference (2-, 3- and 5-fold), the concordance rate of major molecular remission (MMR) and concordance across a range of IS values on paired samples were evaluated.The initial conversion factor for the automated system was determined as 0.43. Except for the second re-validation, where a negative bias of 1.9-fold was detected, all other biases fell within desirable limits. A cartridge-specific conversion factor and efficiency value was introduced and the conversion factor was confirmed to be stable in subsequent re-validation cycles. Concordance with the reference method/laboratory at >0.1-≤10 IS was 78.2% and at ≤0.001 was 80%, compared to 86.8% in the >0.01-≤0.1 IS range. The overall and MMR concordance were 85.7% and 94% respectively, for samples that fell within ±â€Š5-fold of the reference laboratory value over the entire period of study.Conversion factor and performance specific characteristics for the automated system were longitudinally stable in the clinically relevant range, following introduction by the manufacturer of lot specific efficiency values.

Genomic profiling of plasma cell disorders in a clinical setting: integration of microarray and FISH, after CD138 selection of bone marrow.

AIM: To evaluate the role of whole genome comparative genomic hybridisation microarray (array-CGH) in detecting genomic imbalances as compared to conventional karyotype (GTG-analysis) or myeloma specific fluorescence in situ hybridisation (FISH) panel in a diagnostic setting for plasma cell dyscrasia (PCD). METHODS: A myeloma-specific interphase FISH (i-FISH) panel was carried out on CD138 PC-enriched bone marrow (BM) from 20 patients having BM biopsies for evaluation of PCD. Whole genome array-CGH was performed on reference (control) and neoplastic (test patient) genomic DNA extracted from CD138 PC-enriched BM and analysed. RESULTS: Comparison of techniques demonstrated a much higher detection rate of genomic imbalances using array-CGH. Genomic imbalances were detected in 1, 19 and 20 patients using GTG-analysis, i-FISH and array-CGH, respectively. Genomic rearrangements were detected in one patient using GTG-analysis and seven patients using i-FISH, while none were detected using array-CGH. I-FISH was the most sensitive method for detecting gene rearrangements and GTG-analysis was the least sensitive method overall. All copy number aberrations observed in GTG-analysis were detected using array-CGH and i-FISH. CONCLUSIONS: We show that array-CGH performed on CD138-enriched PCs significantly improves the detection of clinically relevant and possibly novel genomic abnormalities in PCD, and thus could be considered as a standard diagnostic technique in combination with IGH rearrangement i-FISH.

Autologous haematopoietic cell transplantation for non-Hodgkin lymphoma with secondary CNS involvement.

Pre-existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non-Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS(+) ) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS(-) ). There were significant baseline differences between the cohorts. CNS(+) patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS(+) group with a subset of CNS(-) patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS(+) patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.

Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research.

The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score ≥90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score ≥90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed.

Outcome of lower-intensity allogeneic transplantation in non-Hodgkin lymphoma after autologous transplantation failure.

We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach.

Impact of pre-transplant rituximab on survival after autologous hematopoietic stem cell transplantation for diffuse large B cell lymphoma.

Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens to treat diffuse large B cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, however, many patients develop refractory or recurrent DLBCL and then undergo autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes after AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n = 176; +R cohort) or was not (n = 818; -R cohort) administered with front-line or salvage therapy before AuHCT. The +R cohort had superior progression-free survival (PFS; 50% vs 38%; P = .008) and overall survival (OS; 57% vs 45%; P = .006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Nonrelapse mortality (NRM) did not differ significantly between the 2 cohorts. In multivariate analysis, the +R cohort had improved PFS (relative risk of relapse/progression or death, 0.64; P < .001) and improved OS (relative risk of death, 0.74; P = .039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival after AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM.

MODELING COST-EFFECTIVENESS OF HIGH DOSE CHEMOTHERAPY AS TREATMENT FOR RELAPSED AGGRESSIVE NON-HODGKIN'S LYMPHOMA IN AN AUSTRALIAN SETTING.

Background: Since 1995 patients with relapsed aggressive non Hodgkin's lymphoma (NHL) have been treated with high dose chemotherapy (HDC) instead of standard dose chemotherapy (SC) because of superior survival demonstrated in the "Parma study". As HDC involves hospital admission and intensive supportive care, the cost of HDC would be predicted to be higher than for SC. The aim of this study was to calculate the Incremental Cost-Effectiveness Ratio (ICER) for HDC compared to SC using Australian costs. Methods: Cost of treatment was determined on 21 pts receiving HDC with characteristics similar to the Parma study from the HDC database of the Calvary Mater Newcastle Hospital (CMNH). Drug, transfusion, inpatient and outpatient attendance and additional relevant data from start of treatment for relapse and up to 100 days following HDC were obtained and costed. SC costs required modelling as all suitable pts are planned to receive HDC if possible, therefore no concurrent SC arms exist. A lifetime estimate of patient-years gained by HDC versus SC was calculated from the area under survival curves (AUC) of HDC and SC. The ICER was calculated according to formula: Incremental Cost / Incremental Benefit = (Costs(HDC)-Costs(SDC)) / (AUC(HDC)-AUC(SDC)). Results: Cost for HDC and SC were $AU37,490 and $AU33,360 respectively, and the AUC(0-infinity) were 4.09 and 3.5 patient life years respectively giving an ICER of $AU7,070 per discounted life year gained. Conclusion Compared to published studies in multiple myeloma and solid organ transplant these results support HDC as a cost-effective treatment in relapsed aggressive NHL.

Influence of age and histology on outcome in adult non-Hodgkin lymphoma patients undergoing autologous hematopoietic cell transplantation (HCT): a report from the Center For International Blood & Marrow Transplant Research (CIBMTR).

To compare the clinical outcomes of older (age > or =55 years) non-Hodgkin lymphoma (NHL) patients with younger NHL patients (<55 years) receiving autologous hematopoietic cell transplantation (HCT) while adjusting for patient-, disease-, and treatment-related variables, we compared autologous HCT outcomes in 805 NHL patients aged > or =55 years to 1949 NHL patients <55 years during the years 1990-2000 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). In multivariate analysis, older patients with aggressive histologies were 1.86 times (95% confidence interval [CI] 1.43-2.43, P < .001) more likely than younger patients to experience treatment-related mortality (TRM). Relative death risks were 1.33 times (CI 1.04-1.71, P = .024) and 1.50 times (CI 1.33-16.9, P < .001) higher in older compared to younger patients with follicular grade I/II and aggressive histologies, respectively. Autologous HCT in older NHL patients is feasible, but most disease-related outcomes are statistically inferior to younger patients. Studies addressing supportive care particular to older patients, who are most likely to benefit from this approach, are recommended.

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy.

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.