High Degree of Hematological Response After Pegylated Interferon Alpha-2a Therapy In Myeloproliferative Neoplasms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5055-5055
Author(s):  
Jan Samuelsson ◽  
Gerd Larfars ◽  
Eva Ottosson ◽  
Mats Merup
Keyword(s):  
Side Effects ◽  
Median Time ◽  
Response Rate ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
Molecular Response ◽  
Hematological Response ◽  
Ifn Therapy

Abstract Abstract 5055 Objective: To retrospectively assess hematological response rates, and other clinical and molecular variables, in MPN patients treated with pegylated interferon α-2a (Pegasys®, Roche Ltd). Responses were graded according to criteria published by the European Leukemia Net for PV and ET (Barosi G et al Blood 2009;113:4829), with the exception that mesurement of spleen size using ultrasound was not routinely performed, and the European Myelofibrosis Network for PMF (Barosi G et al Blood 2005;106:2849), respectively. Patient characteristics: The 23 patient cohort consisted of 13 PV, 5 ET, 3 PMF and 2 post-ET/PV MF pts. Thirteen pts were JAK2V617F+, 6 were JAK2V617F wt, and in 4 pts JAK2 status is unknown. Median age was 50 years (range 26–69), 13 were female and 10 male. Median time from MPN diagnosis to start of pegylated interferon α-2a (Peg-IFN) therapy was 67 months (range 0–204). Six pts had a previous thrombotic event (TIA=2, portal vein thrombosis=2, DVT lower extremity=2), and 2 pts had a previous major hemorrhage (gynecological=1, gastrointestinal=1). Eleven pts had previously received therapy with anagrelide (n=8), hydroxyurea (n=4), interferon α-2b (n=1), busulfan (n=1) or P32 (n=1), while 12 pts had not received bone marrow suppressive therapy. All PV and ET pts were on aspirin. Phlebotomies were performed in PV with the aim of keeping the hematocrit < 0.45. Peg-IFN was given at a dose of 90 μg/week in 16 pts, 135μg/week in 6, and 180μg/week in 1. Results: The overall hematological response rate (CR+PR) was 18/21 (86 %), 14 pts achieving CR and 4 PR. Two pts are too early to evaluate at the time of astract submission. One PV and 1 PMF patient were non-responders. Resonse rates were similar in PV vs ET, female vs male pts, and previously treated vs previously untreated pts. Median time of follow-up on Peg-IFN therapy is 16 months (3+ - 49+). Thirteen pts are still on therapy, 9 in CR, 2 in PR, and 2 too early to evaluate. These 13 pts have very limited or no side effects. Therapy has also been stopped according to plan after long hematological CR with molecular response in 2 pts. Therapy has been discontinued in 8 pts, in five (22 %) due to side effects (depression n=3, joint pain n=3, hair loss n=2, pruritus n=1), non-response in 2 pts, and PMF progression in 1. Serial JAK2V617F measurements are available at time of abstract submission in 4 pts, 1 achieved molecular CR, 2 PR whereas 1 patient treated for 5 months had no molecular response. Three of 4 mildly anemic MF pts normalized their hemoglobin (HgB 113 → 137, 106 → 123, and 110 → 125 respectively). In one PMF patent a clear reduction of marrow fibrosis was noted, whereas it progressed in another. No thromboembolic or bleeding complications were observed during PEG-IFN therapy. Longer follow-up, as well as additional molecular and morphological studies will be presented. Conclusions: Pegylated interferon α-2a induced a higher hematological response rate with improved tolerability, compared to our previous experience with Peg-IFN α-2b (Samuelsson et al Cancer 2006;106:2397), although the current number of patients is limited. However, the two previous publications that describes Peg-IFN α-2a therapy in larger MPN patients cohorts have observed results similar to ours (Kiladjian JJ et al Blood. 2008;112:3065, Quintás-Cardama A et al J Clin Oncol. 2009;27:5418). Molecular responses noted in a subset of patients further highlights the effect of Peg-IFN α-2a on the malignant clone in MPN:s. Peg-IFN α-2a is a valuable therapeutic alternative in patients who tolerate initial side effects, and will soon be compared to hydroxyurea in a randomized trial in high-risk PV and ET pts performed by the MPD research consortium. Disclosures: Samuelsson: Roche Sweden: Advisory board on use of recombinant erytropoetin. Off Label Use: Alpha-interferon does not have a label for use in myeloproliferative neoplasms. Merup:Roche Sweden: Received honoraria for lectures on rituximab use in lymphoma.

Molecular Long-Term Surveillance of CML Patients on Imatinib Therapy. Follow-Up of German Patients Treated within the IRIS Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1003-1003
Author(s):  
Martin C. Mueller ◽  
P. Paschka ◽  
T. Lahaye ◽  
Ch. Lorentz ◽  
N. Gattermann ◽  
...  
Keyword(s):  
Median Time ◽  
Nested Pcr ◽  
Residual Disease ◽  
Response To Therapy ◽  
Imatinib Therapy ◽  
Interferon Α ◽  
Tyrosine Kinase Domain ◽  
Molecular Response

Abstract High rates of complete cytogenetic response (CCR), the availability of sensitive methods to detect residual disease, and direct therapeutic consequences are leading motives to integrate regular molecular monitoring into the standards for the management of patients (pts) with chronic myeloid leukemia (CML). We sought to determine long-term dynamics of BCR-ABL mRNA expression levels in 132 CML pts (75 m, 57 f, median age 51, range 20–71 yrs) recruited into the IRIS study in 17 German centers. Pts were randomized to receive imatinib (n=69) or interferon α+Ara-C (IFN, n=63). Due to intolerance or lack of response 41 pts crossed over from IFN to imatinib. Response to therapy was sequentially monitored by conventional cytogenetics from bone marrow metaphases (n=806). BCR-ABL transcripts were determined in 1414 peripheral blood samples by quantitative real time RT-PCR (RQ-PCR) using the LightCycler technology. In case of low level (&lt;10 transcripts/2μl cDNA) or neg RQ-PCR, nested PCR was performed. Total ABL transcripts were quantified as internal controls. A single series of BCR-ABL plasmid dilutions served as standard for both BCR-ABL and ABL transcripts. In pts on 1st-line imatinib therapy median ratios BCR-ABL/ABL gradually decreased: 4.8% at mo 3, 0.88% at mo 6, 0.22% at mo 12, 0.17% at mo 18, 0.058% at mo 24, 0.066% at mo 30, and 0.023% at mo 36. After crossover to imatinib results were not significantly different: 15.5% at mo 3, 1.6% at mo 6, 0.28% at mo 12, 0.068% at mo 18, 0.045% at mo 24, and 0.041% at mo 30. After a median follow-up of 40 mo (1–47) 31/69 pts (45%) on 1st-line imatinib were still RQ-PCR pos, 20 pts (29%) were RQ-PCR neg and nested PCR pos, and in 4 pts (5.8%) BCR-ABL became undetectable by RQ- and nested PCR. After a median time of 25 mo (3–43) on 2nd-line imatinib therapy 19/41 pts (46%) were RQ-PCR pos, 9 pts (22%) were RQ-PCR neg and nested PCR pos, and in 5 pts (12%) BCR-ABL was undetectable by RQ- and nested PCR. Considering adequate RNA quality BCR-ABL became repeatedly undetectable in 4 pts after 18–33 mo of 1st-line imatinib therapy and in 5 pts 9–33 mo after crossover from IFN to imatinib. In one patient, BCR-ABL remained undetectable after a treatment free interval of 4 weeks. After achieving CCR, 5 pts (7.2%) on 1st-line and 2 pts (4.9%) on 2nd-line imatinib therapy experienced cytogenetic relapse after a median time of 10 mo (4–21). In none of these pts mutations of the tyrosine kinase domain of BCR-ABL were detected. BCR-ABL/ABL ratios after 12 mo of imatinib therapy were significantly lower in pts in continuous CCR vs pts with subsequent relapse (0.18 vs 0.60%, respectively, p=0.04). None of the relapsing patients had achieved a ratio BCR-ABL/ABL &lt;0.12% after 12 mo, which represents a 3-log reduction from baseline. During total follow-up ratios BCR-ABL/ABL &lt;0.12% have been achieved in 51 pts (74%) on 1st-line and in 21 pts (51%) on 2nd-line imatinib therapy. We conclude that (i) treatment with imatinib in newly diagnosed CML pts is associated with a rapid and steady decrease of BCR-ABL transcript levels, (ii) a short trial of IFN does not jeopardize molecular response to subsequent imatinib therapy, (iii) an increasing minority of pts achieve complete molecular remission, and (iv) ratios of BCR-ABL/ABL &lt;0.12% after 12 mo of therapy predict for long-term response.

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Bruno Cassinat ◽  
Sylvie Chevret ◽  
Pascal Turlure ◽  
Nathalie Cambier ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Residual Disease ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
First Year ◽  
Molecular Response ◽  
Sequential Samples ◽  
Low Toxicity ◽  
Pegylated Interferon Alfa

Abstract Interferon-α (IFN-α) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-α-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-α-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6+ to 18+ months, and persisted after pegylated IFN-α-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-α-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

Histomorphological Responses after Therapy with Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4266-4266
Author(s):  
Lucia Masarova ◽  
C. Cameron Yin ◽  
Jorge E. Cortes ◽  
Marina Konopleva ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Response Assessment ◽  
Pegylated Interferon ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Pegylated Interferon Alpha ◽  
Normal Morphology

Abstract Introduction: We previously reported the long-term efficacy and safety of pegylated interferon alpha-2a (PEG-IFN-a-2a) in 83 patients with ET and PV after a median follow-up of 83 months. Here, we present the bone marrow (BM) response assessment according to modified International Working Group for-Myeloproliferative Neoplasms Research and Treatment (IWG-MPN). Objective: To identify histomorphological BM responses in patients with ET and PV treated with PEG-IFN-a-2a as part of a prospective phase II study. Methods: All patients had BM assessment done prior to their enrollment, and then every 6-12 months while on study if possible, and in some patients after treatment discontinuation. Complete BM remission (BM-CR) required absence of > grade 1 reticulin fibrosis and disappearance of megakaryocyte hyperplasia in ET or trilinear hyperplasia with age-adjusted normocellularity in PV. An incomplete, partial response (BM-PR), was defined when fibrosis grading had consistently improved by at least one grade level on at least 2 consecutive samples > 12 months apart, yet with persistent MPN morphological features. Hematologic (HR) and molecular response (MR) assessments were previously reported (ASH 2015, abstract #60). Results: Among 83 enrolled patients (43 PV, 40 ET), 58 patients (70%) had evaluable BM samples for histomorphological response assessment, with median number of 8 samples per patient (range, 3-12). Among the remaining 25 patients, 18 were treated ≤12 months, and 7 did not have representative samples. Median age was 52 years (range, 19-75), and 29% (n=17) were males. Median disease duration prior to enrollment was 31 months (range, 1-350), and the median exposure to PEG-IFN-a-2a was 80 months (range, 15-107). After a median follow-up of 84 months (range, 36-107), 32 patients are on study. Forty-two patients were JAK2 positive, 6 CALR positive, 2 MPL positive and 8 triple negative (TN). Hematologic and molecular (JAK2V617F mutation only) responses were seen in 54 (93%) and 29 (69% of JAK2V617F positive) patients, including complete HR and complete MR in 52 (90%) and 9 (31%) patients, respectively. In total, 29 evaluable patients (50%) had BM response, including 13 patients (22%) with BM-CR (MF-0 in 11, example in Figure 1). Among 16 patients with BM-PR, 3 had resolution of dense collagen bundles as well as decreased reticulin fibrosis. Except for increased platelets in those with BM-PR (p<0.001), likely due to the higher proportion of ET patients in that group, no other differences in basic demographic or clinical parameters were present among different response groups (Table 1). Patients with BM response (PR & CR) had lower discontinuation rate, higher duration of response (HR & MR) with longer time on therapy; 13 patients with BM-CR had higher probability of complete MR (Table 1). Median time to BM-CR was 48 months (range, 30-72), median duration was 30 months (24-52), and has been maintained in 9 patients (69%). Two patients who lost their BM-CR are still on active therapy with persistent complete MR. Interestingly, 4 patients achieved BM-CR after being off therapy for a median of 18 months (range, 2-30), and 3 of them have sustained the BM-CR for 24, 50 and 52 months. Conclusions: Histomorphological BM responses (including complete response) can occur in ET/PV patients treated with PEG-IFN-a-2a, and generally correlate with more durable treatment benefit. Complete BM responses may be sustained even after treatment discontinuation, or be seen after therapy discontinuation. Despite this, we could not identify a uniform correlation between hematologic, histomorphological and molecular response. Table Patients with BM assessment stratified by response, N=58 Table. Patients with BM assessment stratified by response, N=58 Figure BM assessment of a PV patient with BM-CR. A & C: Before treatment: increased cellularity and abnormal megakaryocytes number/morphology; MF-2. B & D: After treatment: normocellular BM, normal morphology, MF-0. Figure. BM assessment of a PV patient with BM-CR. A & C: Before treatment: increased cellularity and abnormal megakaryocytes number/morphology; MF-2. B & D: After treatment: normocellular BM, normal morphology, MF-0. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

Complete Hematological, Molecular and Histological Remissions without Cytoreductive Treatment Lasting After Pegylated-Interferon α-2a (peg-IFNα-2a) Therapy in Polycythemia Vera (PV): Long Term Results of a Phase 2 Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 280-280 ◽  
Author(s):  
Pascal Turlure ◽  
Nathalie Cambier ◽  
Murielle Roussel ◽  
Sylvia Bellucci ◽  
Jean-Marc Zini ◽  
...  
Keyword(s):  
Median Time ◽  
Pegylated Interferon ◽  
Long Term Results ◽  
Molecular Response ◽  
Phase 2 ◽  
Total Cohort ◽  
Hematological Response ◽  
Phase 2 Study ◽  
Cytoreductive Treatment

Abstract Abstract 280 Background: Two phase 2 studies have recently shown promising results of peg-IFNα-2a therapy in PV and essential thrombocythemia, including major efficacy, satisfactory tolerance, and significant molecular responses, renewing the interest for IFNα therapy in patients (pts) with MPN. However, no prospective study has assessed the long-term safety and efficacy of IFN therapy in those pts. We analyzed the long-term results of the PVN1 trial (www.clinicaltrials.gov #NCT00241241), a phase 2 study of peg-IFNα-2a therapy in PV, after a median follow-up (FU) of 6.4 years. Patients and methods: 40 PV pts were enrolled in the study between Sept 04 and Sept 05. 4 pts were not evaluable (1 inclusion criteria violation, 2 withdraws of consent, 1 allergic reaction at first injection). Median age was 50 yrs (range 22–65). Median time since diagnosis was 6 months (range 1–65). 9 pts (25%) had previously received hydroxyurea. 6 pts (17%) had a history of thrombosis. 7 pts (20%) had splenomegaly. Long-term analyses were performed in 34 patients in June 11 (2 pts lost to FU). Hematological, molecular and histological responses were assessed according to the European LeukemiaNet (ELN) criteria. Results: Median FU was 77.4 months (mos) (Q1−Q3: 72 – 81 mos) and median duration of peg-IFNα-2a therapy was 47.4 mos (Q1-Q3: 28 – 77 mos). Clinical-hematological efficacy: At last evaluation, 32/34 pts (94%) were in hematological response including 28/34 complete responses (CR) (82%) and 4 partial responses (PR), and 2 pts had relapsed. 14 pts (41%) were still treated with peg-IFNα-2a for a median time of 70 mos. During FU, 20 pts stopped IFN after having received the drug for a median time of 42 mos. Among them, 10 pts (29% of the total cohort) had stopped because of sustained hematological CR, 8 (23%) because of toxicity, and 2 (6%) at investigator's discretion. 13 (38% of the total cohort) of the 20 pts who stopped therapy did not received any other cytoreductive treatment after peg-IFNα-2a discontinuation, and 10/13 were still in hematological CR off-therapy at last evaluation after a mean observation period of 28+ mos (range 3+ – 64+ mos). During FU, PV relapsed in 3/13 pts who had stopped cytoreductive therapy after a mean time of 25 mos (range 6 – 37 mos). Peg-IFNα-2a was restarted in 2 of them and a second hematological CR was achieved. None of the patients experienced any vascular event during FU, when about 10 events would have been expected in this series of 34 PV pts followed for 77 mos (5.5% pts/year in the ECLAP study). Molecular and histological responses: Molecular response was assessed by measuring JAK2V617F allele burden in granulocytes (%V617F) in 29 pts with serial samples: a molecular response was achieved in 24 pts (83%) including 8 molecular CR (28%), and only 5 pts (17%) had no decrease in their %V617F. Mean %V617F was 47% (range 10 – 100%) at baseline, and 10% (range 0 – 45%) at 72 mos. 4 pts had a TET2 mutation: in none of them the TET2 mutant allele burden decreased during therapy although median decrease in %V617F in the same samples was 100% (Q1 – Q3: 75% – 100%). Bone marrow biopsies performed in some pts in hematological CR after discontinuation of peg-IFNα-2a found a normalized BM morphology fulfilling the ELN criteria for histological CR, and excluded an evolution to myelofibrosis as a cause for “apparent” remission. Toxicity: Peg-IFNα-2a was stopped because of adverse event in 8 pts (23%): fatigue in 2, depression in 1, grade 2 neuropathy in 1, arthralgia in 1, thyroiditis in 1, auto-antibodies in 1, liver enzyme elevation in 1 pt, respectively. Importantly, no unexpected adverse event was observed in spite of the very long-term use of peg-IFNα-2a (median of 45.5 mos). Conclusion: In this prospective phase 2 study of PV pts treated with peg-IFNα-2a after 6.4 years median FU, we recognized that: 1) 94% of pts were still in hematological response, including 82% CR; 2) 29% of pts could stop peg-IFNα-2a and remained in hematological response without further cytoreductive therapy after a median observation time of 28+ mos (up to 64+ mos); 3) major and sustained molecular response in %V617F was confirmed in 83% of patients, including 28% who achieved complete molecular response, while TET2 mutated clones appeared resistant to peg-IFNα-2a; 4) histological CR was also achieved in selected patients; 5) no vascular event was observed after 6.4 years median FU; 6) no new safety concern arose with prolonged utilization of peg-IFN alpha-2a. Disclosures: Off Label Use: Phase 2 study of pegylated-Interferon alpha-2a in polycythemia vera (off-label).

scholarly journals Hyperbaric Oxygen for Radiation Necrosis of the Brain

2019 ◽  
Vol 47 (1) ◽  
pp. 92-99
Author(s):  
Jayson Co ◽  
Marcus Vinicius De Moraes ◽  
Rita Katznelson ◽  
A. Wayne Evans ◽  
David Shultz ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Improvement ◽  
Median Time ◽  
Hyperbaric Oxygen ◽  
Demographic Data ◽  
Symptom Improvement ◽  
Presenting Symptoms ◽  
Transient Improvement ◽  
Brain Radiation

Abstract:Introduction:Hyperbaric oxygen therapy (HBOT) shows promising results in treating radionecrosis (RN) but there is limited evidence for its use in brain RN. The purpose of this study is to report the outcomes of using HBOT for symptomatic brain RN at a single institution.Methods:This was a retrospective review of patients with symptomatic brain RN between 2008 and 2018 and was treated with HBOT. Demographic data, steroid use, clinical response, radiologic response and toxicities were collected. The index time for analysis was the first day of HBOT. The primary endpoint was clinical improvement of a presenting symptom, including steroid dose reduction.Results:Thirteen patients who received HBOT for symptomatic RN were included. The median time from last brain radiation therapy to presenting symptoms of brain RN was 6 months. Twelve patients (92%) had clinical improvement with median time to symptom improvement of 33 days (range 1–109 days). One patient had transient improvement after HBOT but had recurrent symptomatic RN at 12 months. Of the eight patients with evaluable follow-up MRI, four patients had radiological improvement while four had stable necrosis appearance. Two patients had subsequent deterioration in MRI appearances, one each in the background of initial radiologic improvement and stability. Median survival was 15 months with median follow-up of 10 months. Seven patients reported side effects attributable to HBOT (54%), four of which were otologic in origin.Conclusions:HBOT is a safe and effective treatment for brain RN. HBOT showed clinical and radiologic improvement or stability in most patients. Prospective studies to further evaluate the effectiveness and side effects of HBOT are needed.

Comparison of Haematologic Side Effects of Different Pegylated Interferon-α Molecules Combined With Ribavirin

2015 ◽  
Vol 27 (3) ◽  
pp. 99-102
Author(s):  
Mehtap Aydin ◽  
Elif Aksoz ◽  
Oguzhan Korkut ◽  
Sila Akhan
Keyword(s):  
Side Effects ◽  
Pegylated Interferon ◽  
Interferon Α

Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2128-2128
Author(s):  
Jean-Francois Rossi ◽  
A. Van Hoof ◽  
K. De Boeck ◽  
S. A. Johnson ◽  
D. Bron ◽  
...  
Keyword(s):  
Disease Progression ◽  
Median Time ◽  
Response Rate ◽  
Time To Progression ◽  
Open Label ◽  
Overall Response ◽  
Fludarabine Phosphate ◽  
Duration Of Response ◽  
Grade 3

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.

Randomized Comparison of Cladribine Containing Regimens and COP in Previously Untreated Patients with Small Lymphocytic, Marginal Zone and Follicular Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4739-4739
Author(s):  
Ewa Kalinka ◽  
Jaroslaw Wajs ◽  
Kazimierz Sulek ◽  
Tadeusz Robak ◽  
Maria Blasinska-Morawiec ◽  
...  
Keyword(s):  
Side Effects ◽  
Overall Response Rate ◽  
Marginal Zone ◽  
Response Rate ◽  
Low Grade ◽  
Front Line ◽  
Histological Subtypes ◽  
First Line ◽  
To Receive

Abstract The aim of the study was to comparatively assess first-line treatment with cladribine alone or in combination with cyclophosphamide (CCR, cladribine-containing regimens) and COP (cyclophosphamide, vincristine, prednisone) in different subtypes of low-grade lymphoma. End points were complete remission (CR), overall response rate (ORR), incidence of chemotherapy-related side effects as well as freedom from progression (FFP) and overall survival (OS). From June’2000 to June’2005, 178 previously untreated patients (pts) were randomly allocated to receive 6 monthly courses of either CCR or COP in 17 centers in Poland. This analysis included 107 pts who have completed scheduled chemotherapy, including 45 pts with small lymphocytic (SLL, median age=64 years), 26 marginal zone (MZL, median age=58 years) and 36 follicular (FL, median age=65 years) lymphoma. Compared to COP, CCR induced higher CR rates in all treated groups (65% vs 15%, p=.005; 57% vs 10%, p=.02; 58% vs 12%, p=.03, respectively) but differences in ORR were not significant (92% vs 69%; 92% vs 60%; 79% vs 62%, respectively). Incidence of side effects did not differ significantly in CCR- as compared to COP-treated pts, e.i. infections (10% vs 7%; 14% vs 20%; 15% vs 0%, respectively), myelosuppression (31% vs 7%; 21% vs 20%; 30% vs 0%, respectively), and non-hematological adverse events (10% vs 14%; 7% vs 30%; 7% vs 22%, respectively). With a median follow-up of 12 months, median FFP was superior in CCR- as compared to COP-treated treated pts with SLL (43 vs 12 months, log-rank p<.03) or MZL (37 vs 7 months, log-rank p<.03) but not with FL (17 vs 22 months). Although the median OS has not been reached in any of the histological group so far, no difference in its duration is detected between CCR- or COP-treated pts. In summary, for pts with SLL, MZL and FL, first-line CCR regimens provided better CR and similar toxicity rates as compared to COP, which translated into longer FFP in SLL and MZL but not in FL pts. Although these results warrant larger number of pts and longer follow-up, they might suggest the choice of different front-line chemotherapy with or without immunotherapy in particular histological subtypes of low-grade lymphoma.

Long-Term Follow-Up of Patients Treated with Bortezomib Alone and in Combination with Dexamethasone as Frontline Therapy for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 796-796 ◽  
Author(s):  
Sundar Jagannath ◽  
Brian G.M. Durie ◽  
Jeffrey Lee Wolf ◽  
Elber S. Camacho ◽  
David Irwin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Survival Rate ◽  
Median Time ◽  
Response Rate ◽  
Sensory Neuropathy ◽  
High Response Rate ◽  
High Dose ◽  
Phase 2 ◽  
Frontline Therapy

Abstract Introduction: Novel therapeutic agents, such as bortezomib (VELCADE®; btz), thalidomide, and lenalidomide, are being used in combination with dexamethasone (dex) as frontline therapies in MM. Phase 2 and 3 trials with limited follow-up have reported a high response rate and feasibility of high-dose therapy and stem cell transplantation (HDT-SCT). Here we present longer follow-up on our phase 2 trial of btz±dex as frontline therapy. Methods: Patients (pts) with measurable disease and KPS ≥50% received btz 1.3mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle for up to 6 cycles. Oral dex 40mg was added on the day of and day after btz for pts achieving &lt; partial response (PR) after 2 cycles or &lt; complete response (CR) after 4 cycles. Responses were assessed using European Group for Blood and Marrow Transplantation criteria, with the addition of near CR (nCR; CR but positive immunofixation). Results: 48 pts were accrued and were evaluable for response; a further 2 registered on the trial declined to proceed. Median age was 60 years, 46% were male, 64% had IgG and 21% IgA, and 50% were Durie-Salmon stage III. At the end of btz±dex treatment, overall response rate (ORR; CR+nCR+PR) was 90% with 19% CR/nCR; an additional 8% achieved a minimal response (MR). Response to btz alone was rapid; response rate by end of cycle 2 was 50%, including 10% CR/nCR. Dex was added for 36 (75%) pts: 17 at cycle 3, 18 at cycle 5, and 1 at cycle 6. Addition of dex improved best responses to btz in 23 (64%) pts, with 12 improving from stable disease to MR or PR, 9 from MR to PR, 1 from PR to nCR, and 1 from nCR to CR. Median time to best response was 1.9 months. For all 48 pts, with a median follow-up of 24 months, median time to alternative therapy (TTAT) was 7 months (range: 2–25; this includes pts who went on to HDT-SCT), and median overall survival (OS) has not been reached; 1-year survival rate was 90%. For pts not proceeding to HDT-SCT, median TTAT was 22 months, median OS has not been reached; 1-year survival rate was 80%. 23/48 pts proceeded to HDT-SCT. Median CD34+ harvest was 12.6 x 106 cells/kg (range: 5.1–40.4 x 106) from a median of 2 collection days (range: 1–8). All pts had complete hematologic recovery; median time to neutrophil (ANC &gt;1000/mm3) and platelet (&gt;100,000/mm3) engraftment was 11 days (range: 8–13) and 17 days (range: 10–98), respectively. In the 23 HDT-SCT pts, median TTAT and OS have not been reached; post-transplant 1-year survival rate was 90%. The most common grade ≥2 adverse events for btz±dex were sensory neuropathy/neuropathic pain (37%), fatigue (20%), constipation (16%), nausea (12%), and neutropenia (12%). Two pts developed grade 4 events (1 neutropenia, 1 thrombocytopenia). Conclusion: Btz±dex is an effective frontline therapy for MM, with an ORR of 90%, including 19% CR/nCR, and OS rate of 80% at 1 year. The treatment is well tolerated and toxicities were manageable and reversible. Addition of dex to btz provides improved responses. TTAT for patients not undergoing HDT-SCT was 22 months. The regimen does not prejudice subsequent HDT-SCT; stem cell harvest and engraftment were successful in all pts proceeding to transplant. Consolidation with HDT-SCT further increases the response rate and durability of response. Btz+dex is being compared to VAD as induction therapy prior to HDT-SCT in a phase 3 study.

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