The effect of tyrosine kinase inhibitor interruption and interferon use on pregnancy outcomes and long-term disease control in chronic myeloid leukemia.

The management of CML in pregnancy is challenging with the need to balance disease control against potential teratogenic effects of TKI therapy. In this multi-center case-cohort study of 16 women in chronic phase, CML ceased TKI treatment pre- or post-conception during their first pregnancy. Thirteen patients were on imatinib; 9 ceased their TKI prior to conception and 7 ceased at pregnancy confirmation. Twelve patients had achieved either MMR or better at time of TKI cessation. Eleven women lost MMR during pregnancy and two patients lost CHR. Fourteen women reestablished MMR on TKI recommenced. The depth molecular response prior to conception appeared to correlate well with restoration of disease control on TKI recommencement though duration of MMR did not appear to be as important. While interruption of TKI treatment for pregnancy usually leads to loss of molecular response, loss of hematological response is uncommon and disease control is reestablished with resumption of therapy in the majority of women.

Limited clinical benefit for surveillance PET-CT scanning in patients with histologically transformed lymphoma in complete metabolic remission following primary therapy.

The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67 %) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77 % (95 %CI 62-86 %) and 88 % (75-94 %), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94 %, sensitivity was 83 %, positive predictive value was 63 % and negative predictive value was 98 %. All seven subclinical (PET detected) relapses were of low-grade histology; in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.

A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial.

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma.

We report results from a study exploring the combination of romidepsin, bortezomib, and dexamethasone for the treatment of patients with multiple myeloma (MM) previously treated with > 1 prior therapy. The primary objective was to determine the maximum tolerated dose (MTD) of the combination using a novel accelerated dose-escalation schedule in patients with relapsed or refractory MM. The secondary objective was to determine overall response (OR), time to progression (TTP), and overall survival (OS). The MTD identified was bortezomib 1.3 mg/m(2) (days 1, 4, 8, and 11), dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12), and romidepsin 10 mg/m(2) (days 1, 8, and 15) every 28 days. Thrombocytopenia (64%) was the most common ≥ grade 3 hematologic toxicity. Peripheral neuropathy occurred in 76% of patients (n = 19) (≥ grade 3, 8%; 95% confidence interval [CI] 1%-26%). Maintenance romidepsin 10 mg/m(2) (on days 1 and 8 of a 28-day cycle) proved feasible, with 12 patients receiving a median of 7.5 cycles (range: 1-29). An OR (M-protein) of > minor response (MR) was seen in 18 of 25 patients (72%); 2 (8%) had complete remissions (CRs) and 13 (52%) had partial responses (PRs), including 7 (28%) with very good PRs (VGPRs). The median TTP was 7.2 (95% CI: 5.5-19.6) months, and the median OS was > 36 months. This regimen shows activity with manageable toxicity and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as NCT00431990.

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.

[18F]fluorodeoxyglucose positron emission tomography scanning for staging, response assessment, and disease surveillance in patients with mantle cell lymphoma.

BACKGROUND: Positron emission tomography (PET) is an important imaging modality in the staging and response assessment of patients with lymphoma, but data on its specific use in mantle cell lymphoma (MCL) are lacking. PATIENTS AND METHODS: The records of 28 patients with MCL who had a total of 123 [18F]fluorodeoxyglucose (FDG) PET scans between March 1999 and November 2005 were reviewed. Nine patients had staging scans. The other scans were performed for response assessment or relapse surveillance. RESULTS: FDG-PET sensitivity was 100% for nodal disease in the 9 patients studied at baseline. Positron emission tomography scans performed for response assessment were concordant with conventional imaging in 47% and discordant in 53% of cases. Positron emission tomography scanning led to earlier diagnosis of relapse in 1 of 17 patients but produced a high rate of false-negative findings in the evaluation of gastrointestinal involvement. CONCLUSION: FDG-PET appears to be a sensitive modality for staging and for response assessment in MCL but was not found to be useful in relapse surveillance or in the evaluation of gastrointestinal disease.

Early therapeutic response assessment by (18)FDG-positron emission tomography during chemotherapy in patients with diffuse large B-cell lymphoma: isolated residual positivity involving bone is not usually a predictor of subsequent treatment failure.

Residual 2-fluoro-2-deoxyglucose (FDG) - positron emission tomography (PET) positivity during treatment of patients with diffuse large B-cell lymphoma (DLBLC) prospectively identifies a subgroup at high likelihood of subsequent treatment failure. A single institution clinical audit of FDG-PET performance for this indication was undertaken for patients with DLBCL treated with anthracycline-based chemotherapy +/- radiotherapy. Of 45 eligible patients, 14 (31%) were PET-positive after a median of three chemotherapy cycles (range 1 - 5), of which 10 (71%) progressed at a median of 6.5 months. An interim positive PET was a statistically significant adverse prognostic factor for treatment failure (P < 0.0001, log-rank analysis) with a hazard ratio for a positive interim-treatment PET of 9 (95% confidence interval = 4 - 55) and positive predictive value of 71% and negative predictive value of 90%. Notably, four patients with low-grade FDG-avidity limited to sites previously involved by biopsy-proven osseous lymphoma, remain progression-free (median follow-up 62 months). Low-grade FDG-avidity on interim restaging at sites of bone involvement by DLBCL at diagnosis, appears to be less predictive of disease progression than residual nodal or extra-nodal soft tissue abnormality by PET.

Complete remission of hairy cell leukemia variant (HCL-v) complicated by red cell aplasia post treatment with rituximab.

Hairy cell leukemia variant (HCL-v) is a rare form of a chronic B-cell lymphoproliferative disorder. Unlike typical hairy cell leukemia (HCL) where the complete response (CR) rate to 2-chlorodeoxyadenosine and 2'-deoxycoformycin can approach about 90%, in HCL-v CR is rare and partial response (PR) occurs in approximately 50% with these agents. Rituximab treatment in relapsed or refractory HCL results in a CR of 13% to 53%, but its use in HCL-v has not been reported in the literature to our knowledge. We describe a patient with HCL-v, whose course was previously complicated by pure red cell aplasia who achieved CR after treatment with rituximab. We also briefly review outcomes of treatments used in HCL-v reported in the current literature.

A phase Ib clinical trial of PV701, a milk-derived protein extract, for the prevention and treatment of oral mucositis in patients undergoing high-dose BEAM chemotherapy.

Despite the best available agents to prevent mucositis, most patients receiving high-dose chemoradiotherapy regimens experience severe mucositis, and new therapies are needed. In this study, we evaluated the safety and tolerability of a milk-derived growth factor extract (PV701 mouthwash) intended to prevent oral mucositis (OM) after carmustine, etoposide, cytosine arabinoside, and melphalan (BEAM) chemotherapy. PV701 mouthwash (15 mL x 13.5 mg/mL) was administered 6 times a day for 12 days, from day--6 to day +5, to patients with lymphoma, who were given BEAM on day--6 to day--2, with autologous stem cells infused on day 0. Dose de-escalation of PV701 was planned if dose-limiting toxicities occurred. The severity and duration of OM, the duration of enteral/parenteral feeding, the requirement for intravenous opiates, and admission to intensive care were recorded. Outcomes were also compared with those of historical control patients. Nine patients received PV701 13.5 mg/mL. PV701 was well tolerated, and no dose-limiting toxicities were observed. Compared with 89 historical controls, the 9 PV701-treated patients had significantly less frequent grade 2 or 3 OM ( P=.0006) and had grade>or=3 OM for an estimated 5 fewer days ( P=.0003). There was a reduction in the need for enteral/parenteral feeding ( P=.012), its duration ( P=.010), and its frequency ( P=.022) and in the duration of intravenous opiates ( P=.0006). We conclude that PV701 mouthwash is readily administered with minimal side effects at a dose of 1215 mg/d, and further investigation of this agent is warranted.

Fluorine-18 fluorodeoxyglucose positron emission tomography, gallium-67 scintigraphy, and conventional staging for Hodgkin's disease and non-Hodgkin's lymphoma.

PURPOSE: To compare fluorine-18 fluorodeoxyglucose positron emission tomography (PET) and gallium scanning with each other and with conventional staging, for patients with Hodgkin's disease or non-Hodgkin's lymphoma. SUBJECTS AND METHODS: Fifty patients had PET, gallium scanning, and conventional staging of newly diagnosed or progressive Hodgkin's disease or non-Hodgkin's lymphoma. Disease sites, stage, and treatment plans were assessed retrospectively. RESULTS: Positron emission tomography and gallium scanning each upstaged 14% of patients (n = 7). Management was altered by PET in 9 cases (18%) and by gallium scanning in 7 (14%, P = 0.6). Disease was evident in 117 sites in 42 patients. The case positivity rate for conventional assessment was 90%; for PET, 95%; for gallium scanning, 88%; for conventional assessment plus PET, 100%; and for conventional assessment plus gallium scanning, 98%. Site positivity rates for conventional assessment were 68%; for PET, 82%; for gallium scanning, 69% (conventional vs. PET, P = 0.01; conventional vs. gallium scanning, P = 0.9; PET vs. gallium scanning, P = 0.01); for conventional assessment plus PET, 96%; and for conventional assessment plus gallium scanning, 94%. Positron emission tomography and gallium scanning were entirely concordant in 31 patients; in the other 19 patients, PET identified 25 sites missed by gallium scanning, whereas gallium scanning identified 10 sites missed by PET. CONCLUSION: In this retrospective study, PET demonstrated a higher site positivity rate than did gallium scanning, with similar case positivity rates. These data support the use of PET in place of gallium scanning for the staging of patients with Hodgkin's disease or non-Hodgkin's lymphoma.