Phase II study of pegylated liposomal doxorubicin (PLD), low-dose dexamethasone (DEX), and lenalidomide (LEN) in patients with newly diagnosed (ND) multiple myeloma (MM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8518-8518
Author(s):  
R. Baz ◽  
M. A. Hussein ◽  
D. Sullivan ◽  
J. Raychaudhuri ◽  
L. Ochoa ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
High Dose ◽  
Hematologic Toxicity ◽  
High Dose Therapy ◽  
Overall Response ◽  
Dose Therapy ◽  
Grade 3

8518 Background: We previously reported the results of a phase I/II trial of PLD, low dose DEX and LEN in patients with relapsed and refractory MM in which the MTD of LEN was 10 mg (for 21 of 28 days) and the overall response rate was 75% with 29% of patients achieving nCR or better (Ann Oncol 2006). Accordingly we evaluated this regimen in ND MM. Methods: We hypothesized that patients with ND MM would tolerate this combination better. Accordingly, patients received PLD (40 mg/m2 on day 1), DEX (40 mg on days 1–4) and LEN (25 mg Days 1–21) every 28 days (for 2 cycles beyond best response: 4–8 cycles). Prophylactic low dose aspirin, acyclovir and fluoroquinolone were recommended. Patients not eligible or not wishing to proceed with high dose therapy continued on the tolerated dose of LEN and DEX until disease progression or unacceptable toxicity. Results: Between 2/2008 and 8/2008, 31 of a planned 60 patients were enrolled. 2 patients were screen failures and are not included in subsequent analysis. The mean age was 64 years (41–82) and 58% were males. The median β2microglobulin was 2.8 mg/dL (34% had β2m>3.5). Using the modified SWOG criteria and after a median of 4 cycles of therapy, the overall response rate was 80% with 40% VGPR and better. Two patients had stable disease and 3 patients had progressive disease. Grade 3/4 hematologic toxicity was as follows: neutropenia (48%), anemia (10%), thrombocytopenia (7%). Grade 3/4 non-hematologic toxicity included: Fatigue (21%), infections and febrile neutropenia (20%, only 1 patient with febrile neutropenia), venous thromboembolic events (10%). 14 patients went off study including 8 patients to proceed with high dose therapy. Conclusions: The combination of PLD, LEN and DEX is an active regimen in patients with ND MM. Due to the unexpected higher rates of neutropenia and fatigue, the dose of PLD will be decreased to 30 mg/m2 every 28 days. Updated results will be presented at the time of the meeting. [Table: see text]

scholarly journals Observational Study Alternating R-CHOP21 and R-Cytarabine (3+3 Cycles) for Patients with Newly Diagnosed Mantle Cell Lymphoma Not Eligible for High-Dose Therapy: A Czech Lymphoma Study Group Trial Preliminary Results

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1720-1720
Author(s):  
Pavel Klener ◽  
Eva Fronkova ◽  
Robert Pytlik ◽  
Marketa Kalinova ◽  
Kristina Forsterova ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Pet Ct ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma characterized by frequent relapses and adverse prognosis. Implementation of high-dose cytarabine (HDAC) and incorporation of anti-CD20 antibody rituximab (R) into induction and maintenance, and consolidation with high-dose therapy and autologous stem cell transplantation (HDT-ASCT) significantly improved pt´s outcome. Therapy of the elderly or comorbid (not eligible for HDT-ASCT) is largely based on R-CHOP or R-bendamustin induction with or without R maintenance. Minimal residual disease (MRD) assessment by quantitative PCR (qPCR) from peripheral blood or bone marrow (BM) has emerged as a powerful molecular marker of outcome. Based on the results of the younger pts some centers adopted the use of HDAC in elderly as well, but no data has been presented yet. Aim: We initiated the observational study as a non-intervention, multi-center trial with the primary objectives to prospectively evaluate efficacy of alternating R-CHOP21 and R-HDAC (1 or 2 g / m2, 2 doses a 24 hours) in newly diagnosed MCL pts not eligible for HDT-ASCT. Methods: Primary endpoints were overall response rate (ORR) by PET-CT, and MRD assessment by qPCR after completion of induction. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. The choice between 1 and 2 g / m2 cytarabine was left at investigator´s discretion, as well as the rituximab maintenance. Patients with known cardiac co-morbidity could be treated with R-COEP (etoposid 50 mg / m2, D1-D3) instead of R-CHOP. Exclusion criteria included eligibility to HDT-ASCT, ECOG≥ 4, and CNS involvement. Results: Altogether 61 pts (38 men and 23 women, ratio 1.7:1) were enrolled into the study between 16-JUN-2011 and 18-MAR-2014. Median age was 70 years both for men and women. 91.5%, and 80% pts presented with stage 3/4 disease, and infiltration of BM, resp. According to the MIPI, 55.7%, 39.4%, and 4.9% pts had high, intermediate and low risk disease, resp. B-symptoms were recorded in 33.3% of pts. 76.8% and 24.2% pts were diagnosed from the lymph node, and trephine biopsy, resp. 62.8%, 27.9%, and 9.3% pts presented with classical, pleomorphic and blastoid variant MCL, resp. Ki67/MIB1 ≥ 30% was observed in 38% of pts. Bulky disease >5cm, and >10cm, was noticed in 31% and 13% pts. Spleen involvement was observed in 53% pts. Extra-nodal involvement other than BM was histologically confirmed in 11.5% pts. R-CHOP was used in 88% pts (12% pts received R-COEP), 86% pts received 2g / m2 cytarabine (14% pts 1g / m2). 86.3% pts with response were treated with R maintenace. Only one patient was excluded from the study due to unacceptable toxicity. 57.7% pts developed grade 3/4 hematologic toxicity (neutropenia, anemia or thrombocytopenia). Grade 3/4 non-hematologic toxicity occurred in 27.3% pts. All pts had PET-CT restaging after completion of induction. Overall response rate (CR+PR) reached 91.7%. CR and PR rate by PET was 76.7%, and 15%, resp. SD, and progression on therapy was noticed in 3.3%, and 5.0%, resp. Samples for MRD assessment were collected from 41 out of 54 pts, who completed induction and achieved response (CR or PR). At the time of abstract submission 21, 7, and 7 (out of 36 so far evaluated pts) were MRD negative, MRD positive-not quantifiable, and MRD positive-quantifiable, resp. With the median follow-up 19.1 month, there were 7 progressions and 6 deaths. 2-year PFS and OS probability were 83.9% and 88.1%. Conclusion: Alternation of R-CHOP and R-HDAC in newly diagnosed elderly or co-morbid MCL pts represents a promising, very effective and well-tolerated treatment approach that induces high ORR, and MRD negativity. Grant Support: IGA-MZ NT/13072-4, PRVOUK-27/LF1/1 Disclosures No relevant conflicts of interest to declare.

SDX-105 Demonstrates a High Response Rate as a Single-Agent with Acceptable Safety in Rituximab-Refractory, Relpased Indolent or Transformed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2480-2480 ◽  
Author(s):  
Jonathan Friedberg ◽  
Philip Cohen ◽  
Robert O. Kerr ◽  
K. Sue Robinson ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Reduction ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Mitotic Catastrophe ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Cell Death Pathway ◽  
Grade 3

Abstract SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of >50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3542-3542 ◽  
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chemotherapeutic Agents ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2713-2713
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

scholarly journals Bromocriptine in Parkinson’s Disease: Results Obtained With High and Low Dose Therapy

1984 ◽  
Vol 11 (S1) ◽  
pp. 225-228 ◽  
Author(s):  
J. David Grimes
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Statistical Analysis ◽  
Low Dose ◽  
Response Rate ◽  
De Novo ◽  
High Dose ◽  
High Dose Therapy ◽  
Treatment Groups ◽  
Dose Therapy

ABSTRACTThe results obtained with high and low dose bromocriptine therapy were compared in a review assessing the per cent of patients showing improvement (not taking account of the extent of improvement). It is concluded that the response rate with low dose bromocriptine is as good as that obtained with high dose therapy for both de novo and levodopa treated patients. The incidence of adverse effects is similar in the high and low dose treatment groups: More levodopa reduction results in a higher daily bromocriptine requirement. A statistical analysis of 61 bromocriptine-levodopa treated patients showed no positive correlation between bromocriptine dose and severity or duration of Parkinson’s disease.

A phase II study of docetaxel and gemcitabine in the treatment of recurrent ovarian, peritoneal, and fallopian tube cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15006-15006
Author(s):  
M. S. Shahin ◽  
P. Hanjani ◽  
S. Nolte
Keyword(s):  
Fallopian Tube ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Fallopian Tube Cancer ◽  
Overall Response ◽  
Platinum Sensitive ◽  
Significant Difference ◽  
Grade 3

15006 Background: The aim of this trial was to investigate the efficacy and toxicity of weekly combination of docetaxel (D) and gemcitabine (G) in the management of recurrent ovarian, peritoneal, or fallopian tube cancer. Methods: D (30 mg/m2) was given as a one-hour IV infusion followed by G (650 mg/m2) as a 30 minute IV infusion on Day 1, 8 & 15 of a 28-day cycle. Results: Thirty pts were enrolled. Mean age was 67.4 (range 47–85). Twelve (40%) pts had Platinum sensitive disease, and 18 (60%) had Platinum resistant disease. One hundred eighteen cycles were evaluable for toxicity. The mean number of cycles was 4 (range 1–7). Twenty-six (22%) of the cycles were incomplete due to toxicity (day # 15 not given in 25 of the incomplete cycles). Dose delay was observed in 4 (13.3%) pts, and a one-dose level reduction was required in 11 (36.7%) pts. Hematologic toxicity included grade 3 neutropenia in 13 (11%) cycles, grade 3 thrombocytopenia in 11 (9.3%) cycles. No grade 4 neutropenia, thrombocytopenia or neutropenic fever was encountered. Bone marrow support with erythropoiten (36.6% pts), and filgrastim (13.3% pts) were utilized. Blood transfusions were given in 10 (8.5%) cycles. Elevated LFT grade 1/2 was seen in 7 (23.3%) pts and 3 (10%) pts, respectively. Nonhematologic grade 3 toxicites occurred in 4 pts (including one seizure). Mean follow-up interval was 19.6 months (mos) (range 1–36.6). To date, 14 (46.6%) pts are alive with disease, and 16 (53.4%) have died of disease. The overall response rate was 32% (1 CR and 8 PR in 28 evaluable pts). Ten pts (33.3%) had SD and 5 had ID. Median progression-free interval (PFI) was 3.8 mos (95% CI: 1.65–5.97). Overall survival was 19.6 mos (95% CI: 14.23–24.96), and no significant differences in PFI and survival between the Platinum-sensitive and resistant pts (P = 0.5, P = 0.08, respectively). Conclusions: Weekly docetaxel plus gemcitabine is an active and tolerable regimen with minimal toxicity in this older population of pts (9 ≥ 80 years of age). No significant difference in response between Platinum sensitive and resistant pts was observed. Overall response rate appears to be better than single agent regimens currently available. Elimination of the third week of treatment may not affect efficacy and will be more acceptable to pts with less toxicity. No significant financial relationships to disclose.

scholarly journals Percutaneous Hepatic Perfusion (PHP) with Melphalan in Liver-Dominant Metastatic Uveal Melanoma: The German Experience

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 118
Author(s):  
Cornelia L. A. Dewald ◽  
Mia-Maria Warnke ◽  
Roland Brüning ◽  
Martin A. Schneider ◽  
Peter Wohlmuth ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Response To Therapy ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Hepatic Perfusion ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Percutaneous Hepatic Perfusion

Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated with PHP. A total of 66 patients with liver-dominant metastasized uveal melanoma, treated with 145 PHP between April 2014 and May 2020, were retrospectively analyzed with regard to adverse events (AEs; CTCAE v5.0), response (overall response rate (ORR)), and disease control rate (DCR) according to RECIST1.1, as well as progression-free and overall survival (PFS and OS). With an ORR of 59% and a DCR of 93.4%, the response was encouraging. After initial PHP, median hepatic PFS was 12.4 (confidence interval (CI) 4–18.4) months and median OS was 18.4 (CI 7–24.6) months. Hematologic toxicity was the most frequent AE (grade 3 or 4 thrombocytopenia after 24.8% of the procedures); less frequent was grade 3 or 4 hepatic toxicity (increased aspartate transaminase (AST) and alanine transaminase (ALT) after 7.6% and 6.9% of the interventions, respectively). Cardiovascular events included four cases of ischemic stroke (2.8%) and one patient with central pulmonary embolism (0.7%). In conclusion, PHP is a safe and effective salvage treatment for liver-dominant metastatic uveal melanoma. Serious AEs—though rare—demand careful patient selection.

Cyclophosphamide Remains An Important Component of Treatment in CLL Patients Receiving Pentostatin and Rituximab Based Chemoimmunotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 43-43 ◽  
Author(s):  
Neil E. Kay ◽  
Wenting Wu ◽  
John C. Byrd ◽  
Brian Kabat ◽  
Diane F. Jelinek ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Patient Characteristics ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Grade 3 ◽  
Ecog Ps ◽  
Experienced Grade

Abstract BACKGROUND: We have previously studied and reported that the combination of pentostatin (P, 2 mg/m2), cyclophosphamide (C 600 mg/m2) and rituximab (R 375 mg/m2) in previously untreated CLL is highly effective with an overall response (OR) rate of over 90% and a complete response rate (CR) of 41% (Blood109:405–411, 2007). We also found that this regimen can be effective even in older patients (>70 y), those with elevated beta-2 microglobulin levels, and patients with mildly reduced creatinine clearances (Cancer. 109:2291–2298, 2007). To determine whether similar benefit could be achieved without inclusion of an alkylating agent, we conducted a follow-up trial testing pentostatin and rituximab without cyclophosphamide and employing a higher pentostatin dose (4 mg/m2). METHODS: Eligible pts had documentation of active CLL by standard NCI-WG criteria, and were previously untreated. Treatment schema consisted of 6 cycles of pentostatin (4 mg/m2) and rituximab given every 21 days. Pentostatin was given on the first day of each cycle following infusion of rituximab. Rituximab was given at 100mg/m2 IV at day 1, then 375 mg/m2 IV on days 3 and 5 of the first treatment cycle. During cycles 2 to 6, Rituximab was given at 375 mg/m2 as a single IV infusion day 1 of week 4, 7, 10, 13 and 16. All patients were staged two months after completion of the 6 cycles of PR using the NCI-WG criteria. PATIENT CHARACTERISTICS: Overall, 33 patients were enrolled at Mayo Clinic and Ohio State University between July 2005 and February 2008. All 33 were eligible: 82% male, median age 65 (range: 45–81), with 9 (27%) being 70 years or older. 76% had a baseline ECOG PS of 0, and the rest were ECOG PS 1. Overall, 36% of patients had intermediate Rai risk (stage I–II) and 63% high Rai risk (stage 3–4) disease. Prognostic testing revealed that 36% were CD38+, 50% were Zap-70 +, and 39% had an unmutated IgVh status. Chromosome analysis by FISH found that 99% had detectable FISH panel defect, including 61%, 27% and 3% of patients with 1, 2, or 3 FISH detects, respectively. RESULTS: 28 of 33 patients (85%) completed therapy. While on treatment, 6 pts (18%) had a dose held or modified with 4 of these delays due to hematologic AE. For adverse events deemed at least possibly related to treatment, 4 (12%) pts experienced grade 3+ hematologic toxicity and 5 (15%) experienced grade 3+ non-hematologic toxicity. Out of all 33 enrolled patients, the overall response rate was 79% with 10 CR, 6 nPR, and 10 PR. At the time of this analysis, 29/33 patients are still alive with a median follow-up time of 14 months on surviving patients. To date 17/33 (52%) of patients have progressed with an estimated median time to progression of 12 months (95% CI: 8.5–21 months). 13/26 responders have progressed. Median duration of response is 12.5 months ((95% CI: 11–21 months). Finally, since eligibility were nearly identical and enrollment accrued at the same two academic centers, we compared the patient characteristics, response rates, and PFS of the 33 patients treated with PR to the 64 patients previously treated on our PCR trial. Patients in the two studies were generally similar with respect to demographic and prognostic characteristics, although patients in the PR trial had higher WBC and were less likely to be IgVH unmutated (Table). Although the differences in ORR and CR rate were not significantly different, the PFS appeared to be inferior in patients treated with PR as compared to PCR (12 months vs. 31 months; p=0.003). CONCLUSION: Although the PR regimen achieves a high OR response rate, the PFS appears inferior to PCR therapy. These findings suggest that increasing the purine nucleoside analogue dose does not eliminate the need to include cyclophosphamide in chemoimmunotherapy for patients with CLL. PCR Trial N=64 PR Trial N=33 P value Age, median(range) 63 years (38–80) 65 years (45–81) 0.34 ≥70 years(%) 28% 27% Male 77% 82% 0.61 Rai stage 0 5% 0 0.46 Rai stage I–II 42% 36% Rai stage III–IV 53% 64% White Cell Count, median(range) 79 × 109/L (11–519) 127 × 109/L (8–430) 0.04 <50 × 109/L 36% 28% 50–149 × 109/L 44% 25% >150 × 109/L 20% 47% Serum B2-microglobulin, median(range) 3.97 (1.8–13.5) 3.80 (2.0–8.2) 0.81 >2 × Upper Limit Normal(%) 57% 58% CD38 Positive 34% 36% 1.00 ZAP-70 Positive 36% 50% 0.26 IgVH Unmutated 71% 39% 0.004 FISH Normal, 11% 9% 13q- 35% 42% +12 21% 24% 6q- 2% 0 11q- 22% 18% 17p- 6% 3% other 3% 3% Overall Response Rate 91% 79% 0.12 Complete Response Rate 41% 30% 0.38 Median PFS 31 months 12 months 0.003

scholarly journals Treatment with Temozolomide and Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Loïc Renaud ◽  
Jean-Baptiste Bossard ◽  
Louis Terriou ◽  
Nathalie Cambier ◽  
Guillaume Chanteau ◽  
...  
Keyword(s):  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Overall Response ◽  
Dose Methotrexate ◽  
Grade 3 ◽  
Cns Lymphomas

I ntroduction Despite recent therapeutic progress in this field, the prognosis of elderly patients with Primary (PCNSL) and Secondary Central Nervous System Lymphoma (SCNSL) remains poor, with a median OS of less than two years in most prospective studies. Patients with chemo refractory relapsed PCNSL within the first year from diagnosis have a median OS of 2-4 months. Activated B cell like subtype of Diffuse Large B Cell Lymphoma (DLBCL) and PCNSL relies on a chronically active B-cell receptor (BCR) signaling. Ibrutinib achieves CNS penetrance and has a high overall response rate in CNS lymphomas, but duration of response is short and curative potential is limited. A novel regimen that combines ibrutinib with temozolomide, etoposide, liposomal doxycycline, dexamethasone, and rituximab (Teddi-R) seems to be promising for this population but its tolerance is an issue in patients with advanced age and poor general condition, common features of many PCNSL patients., calling for an alleviated regimen of broader use. Patients and methods We evaluated a combination of temozolomide and ibrutinib in immunocompetent adult with recurrent/refractory (PCNSL) and (SCNSL) treated in five French centers between June 2015 and January 2020. The treatment consisted of 560 mg ibrutinib orally once daily (28-day cycles) and temozolomide 100 mg/m2 or 150 mg/m2 orally day 1 to 5 for cycle 1, increased to 200mg/m2 day 1 to 5 from cycle 2, until disease progression or unacceptable toxicity occurred. The evaluations were performed using Magnetic resonance imaging (MRI) and the responses were assessed according to the International PCNSL Collaborative Group Response Criteria. The lymphoma diagnoses were all confirmed by expert pathologists in the framework of the national program "lymphopath", based on the criteria of the World Health Organization 2008 classification. Results 22 immunocompetent adults with recurrent/refractory (PCNSL n=13) and (SCNSL n=9) were evaluable for safety and efficacy. Median age was 71 years (range, 44 - 89 years). All patients had relapsed (n=6) or refractory (n=16) disease, after a median of two lines of therapy (range, 1-3). Overall, 18 patients (82%) and 14 (64%) patients had previously received high dose methotrexate or both high dose methotrexate with high dose cytarabine, respectively. Among the four patients who did not receive Methotrexate, one had a chronic kidney disease secondary to diabetic nephropathy and experienced major toxicity after cytarabine infusion. The three others (72, 79 and 89 years old) were SCNSL experiencing comorbidities and toxicities from their previous treatment lines. Ten patients had a poor performance status according to Eastern Cooperative Oncology Group [ECOG] ⩾ 2. Patients received a median of 3.2 cycles (1-19 cycles). One patient received whole brain radiotherapy consolidation after obtaining a partial response under treatment. Best overall response rate was 55% (12/22) including 3 (13.6%) complete responses and 9 (40.9%) partial responses. After a median follow-up of 18.2 months (range, 5.1 - 61.7), the median progression-free survival was 5.3 months (95% confidence interval [CI]; 3.10 - NA) and overall survival 8.9 months (95% CI; 5.2 - NA). Eight patients (36%) received temozolomide and ibrutinib for more than 6 months, four patients were still on treatment at the end of the follow-up including one on ibrutinib only. Twelve patients (55%) stopped treatment due to progressive disease. Three (14%) patients stopped treatment for toxicity: Two (9%) due to grade 2 atrial fibrillation and one patient after 18 months in RC due to grade 1 muscle cramps, which did not stop after treatment discontinuation. three (14%) patients stopped temozolomide only due to recurrent grade 2 microcrystalline arthritis, grade 3 fall and one patient after 15 months in RC due to recurrent grade 2 bronchial infection, asthenia and nausea. Two patients temporary stopped treatment for grade 1 tumor hemorrhage and grade 3 tumor hemorrhage with grade 3 seizure. Micro-bleedings were seen at the MRI in four patients. Four patients (18%) experienced serious infectious complications including: two grade 3 febrile neutropenia, one grade 3 urinary tract infection and one grade 3 sepsis. None of the patients developed aspergillosis during the follow-up. Conclusion Temozolomide combined with ibrutinib showed clinical activity with manageable side effects in R/R CNS lymphomas. Disclosures Morschhauser: Novartis: Honoraria; JANSSEN-CILAG: Honoraria; Pharmacyclics LLC: Honoraria; Gilead: Honoraria; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Servier: Honoraria.

Phase II Trial of Lenalidomide, Cyclophosphamide, and Dexamethasone (CRd) for Newly Diagnosed Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 190-190 ◽  
Author(s):  
Shaji Kumar ◽  
Suzanne R. Hayman ◽  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Keith Stewart ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
M Protein ◽  
Hematological Toxicity ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Grade 3

Abstract Background: The combination of lenalidomide and dexamethasone (Rev/Dex) has been shown to be a highly effective therapy for multiple myeloma (MM). Over half of the patients with newly diagnosed MM achieve a complete response with prolonged therapy. More recently, a phase III trial demonstrated improved survival with use of lenalidomide and low dose dexamethasone with one year survival in excess of 90%. We report the initial results from a phase II trial combining lenalidomide and low dose dexamethasone with cyclophosphamide (CRd) as initial therapy of newly diagnosed MM. Methods: The trial was initiated in July 2006 and completed the target accrual of 33 patients by July 2007. The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone (dex) was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle. Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed at least 4 weeks apart. Results: The median age was 63 years (range, 44–79). Eight patients (24%) had ISS stage III disease. At this time, 19 of the 33 patients are evaluable for confirmed responses (i.e., off-study or completed at least 4 cycles of therapy). Of these, 2 achieved VGPR and 13 had a partial response giving an overall response rate of 79%. The response rate was affected by 5 of 19 patients who went off study within three cycles due to toxicities [interstitial nephritis (1 pt), multiple grade 3 toxicities including infection (1 pt) atrial fibrillation and infection (1 pt)] or alternative treatment [no response and possible renal toxicity (1 pt) and progression at 4 cycles (1 pt)]. Overall, hematological toxicity was the most common with grade 4 toxicity seen in 6 patients (20%). Non-hematological grade 3 or higher toxicities included fatigue (4 pts), thrombosis (3 pts) and renal failure (2 pts). One patient with thrombosis came off study for other toxicities, and the other two continued on study with anticoagulation. Thirteen patients (43%) had dose reductions of both cyclophosphamide and lenalidomide, most commonly due to hematological toxicity. So far, 12 patients have gone off study, 6 went to stem cell transplant, 3 due to adverse events, 1 due to disease progression and 2 patients went to alternate treatment. Conclusions: CRd has excellent activity in newly diagnosed myeloma with an estimated overall response rate of 79%. Response evaluation of the entire 33 patients will be presented at the meeting. We believe that the initial use of a 300 mg/m2 dose of cyclophosphamide resulted in 5 of the first 19 pts experiencing early toxicity and withdrawal. As a result, an expansion of the current trial is evaluating lower doses of cyclophosphamide (300 mg fixed dose). Full analysis of this study will be needed to determine if CRd can improve outcome compared to Rd.

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