Henry Januszewicz

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.

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 Hodgkins disease or non-Hodgkins lymphoma. SUBJECTS AND METHODS Fifty patients had PET, gallium scanning, and conventional staging of newly diagnosed or progressive Hodgkins disease or non-Hodgkins 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 Hodgkins disease or non-Hodgkins lymphoma.

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.

Limited role for surveillance PET–CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy

Background:The usefulness of positron emission tomography with computed tomography (PET–CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied.Methods:We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET–CT after achieving complete metabolic response (CMR) following primary therapy.Results:Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8–133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI⩾3. Including indeterminate scans, PET–CT retained high sensitivity 95% and specificity 97% for relapse.Conclusion:Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ⩾3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

[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.

The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy

BACKGROUND Fludarabine-based chemoimmunotherapy has well-recognised efficacy and short-term toxicity in the treatment of lymphoid malignancies. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly quantified. METHODS Sixty-one patients receiving initial therapy with fludarabine-based regimens were categorised according to the presence of post-treatment cytopenias (haemoglobin <110-130 g/l depending on sex and age, neutrophils <2.0 x 10(9)/l, or platelets <140 x 10(9)/l) lasting >3 months. RESULTS Persistent cytopenias unrelated to persistent disease were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (P = 0.03) and predicted for worse overall survival (61% versus 96% at 60 months, P = 0.05). Increasing age predicted for persistent cytopenias (P = 0.02), but the presence of pretreatment cytopenias and delivered dose intensity were not predictive. The median times to resolution of anaemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively. CONCLUSIONS Cytopenias often persist >3 months after first-line fludarabine combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting treatment response status in chronic lymphocytic leukaemia.

Cure of Pulmonary Rhizomucor Pusillus Infection in a Patient with Hairy-Cell Leukemia: Role of Liposomal Amphotericin B and GM-CSF

We describe a case of successfully treated multifocal pulmonary Rhizomucor pusillus, a condition which has previously been universally fatal. A 77 year-old man had a background of chronic neutropenia due to hairy-cell leukemia, splenectomy, corticosteroid therapy and an obstructing left ureteric transitional-cell carcinoma. He was successfully treated with 3 months of high-dose liposomal amphotericin B and 7 months of granulocyte-macrophage colony-stimulating factor. Treatment was complicated by mild reversible deterioration of renal function. There was a near complete radiological response to the therapy at 6 months and the patient remains well 20 months following diagnosis of R. pusillus and 13 months following cessation of treatment.

Early therapeutic response assessment by 18FDG-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.

A phase II study of dexamethasone, ifosfamide, cisplatin and etoposide (DICE) as salvage chemotherapy for patients with relapsed and refractory lymphoma.

The 4-day combination of dexamethasone, ifosfamide, cisplatin, and etoposide (DICE) is a salvage regimen for lymphoma. We report a prospective phase II multi-center trial of a modified DICE regimen in relapsed or refractory Hodgkin (HL) or non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), constituting a single day of intravenous administration followed by 3 days of oral administration, aimed at reducing inpatient days without losing efficacy. Forty patients (median age 56, range 25 - 79) were included: 28 (70%) NHL, 9 (23%) HL and 3 (8%) CLL. Fifty-three per cent had received ⩾̸ 2 prior treatment regimens. International Prognostic Index (IPI) was ⩾̸ 2 in 75% of NHL patients. Patients aged ⩾̸ 55 and those with previous autologous stem cell transplantation (ASCT) started on a lower-dose regimen, with dose escalation possible in 2 patients. Overall response rate was 41%. Thirty-eight per cent of patients had stable disease. With a median of 3.1 years of follow-up, estimated progression-free survival (PFS) and overall survival (OS) rates at 3 years were 15% and 43% respectively. OS was longer in the < 55 compared to the ⩾̸ 55 age cohort (P = 0.0091), longer for HL than NHL (P = 0.59 and 0.039 respectively) and longer for Low/Low-Int IPI than High/High-Int IPI (P = 0.0074 and 0.0009 respectively). Median duration of inpatient stay was 3 days. There were no treatment-related deaths. In conclusion, this modification of DICE is an effective and well tolerated salvage regimen, even in this poor prognosis group of patients. Further clinical studies of DICE in first relapse and in older patients, possibly with the addition of rituximab, are warranted.

Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte-colony stimulating factor.

Twenty-one patients with advanced chronic myeloid leukemia (late chronic phase (n = 8), accelerated phase (n = 11) and blast crisis (n = 2)) were treated with idarubicin, cytarabine, and etoposide followed by G-CSF and subsequent collection of peripheral blood progenitor cells in the early recovery phase. Treatment was reasonably well tolerated with no deaths or intensive care admissions. Despite the advanced phase of disease and heavy pretreatment with cytotoxics and interferon-alfa, 11 of 21 patients (52%) achieved a cytogenetic response. Of the nine major cytogenetic responses (complete (n = 3) and partial (n = 6)), seven achieved adequate progenitor collections for consideration for autologous transplantation. The only predictor of response was disease duration (P = 0.02). With a median follow-up of 1171 days from treatment it appears unlikely that G-CSF contributed to disease progression. Survival post-IcE was predicted by disease stage (P = 0.0001). Intensive chemotherapy followed by G-CSF allowed adequate yields of predominantly Philadelphia chromosome negative progenitor cells to be obtained from one-third of patients with advanced CML.