Ad-ISF35-Transduced Autologous Cells In Combination with Fludarabine, Cyclophosphamide, Rituximab (FCR) Induces Complete and Partial Responses In a Phase 1b Study for Patients with Fludarabine-Refractory and/or Del(17p)/p53-Defective Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 168-168
Author(s):  
Januario E. Castro ◽  
Lee Schwartzberg ◽  
Javier Pinilla-Ibarz ◽  
Johanna Melo-Cardenas ◽  
Juan S. Barajas-Gamboa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cytotoxic Activity ◽  
Residual Disease ◽  
Complete Response ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Cell Transplant ◽  
Phase 1B

Abstract Abstract 168FN2 CLL cells with del(17p) typically have loss of functional p53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40 ligand (CD154) are induced to express pro-apoptotic factors to overcome resistance to the cytotoxic activity of p53-dependent drugs, such as fludarabine. To examine whether a CD154-based therapeutic strategy can be developed in vivo for del(17p) and/or fludarabine-refractory CLL, a phase 1b clinical study evaluating an autologous cellular gene immunotherapy is being conducted. Autologous CLL cells transduced ex vivo with a replication-defective adenovirus vector encoding a membrane-stable, re-engineered form of CD154 (Ad-ISF35) are administered, followed by standard courses of FCR. Subjects with fludarabine-refractory and/or del(17p) CLL received three IV doses (one dose every two weeks) of 3×108autologous Ad-ISF35-transduced CLL cells. Two weeks following the third dose of Ad-ISF35-transduced cells, subjects receive up to six monthly cycles of FCR. Study endpoints include analysis of safety and efficacy. Nine (9) subjects have been enrolled and treated on study. Median age was 63 (range 48–70). All subjects were del(17p) (range 14–96%), and included treatment naïve (n=4) and previously treated (n=5) subjects. The number of prior treatments range from 0–5, including three subjects that previously received fludarabine-containing regimens. The overall response rate was 67% with 56% of subjects achieving a complete response (CR), including 3 CRu pending bone marrow assessment. Two subjects with a marked percentage del(17p) (range 63–66%) continue to have an ongoing complete response (CR) after a median follow up of >2 years, and no detectable minimal residual disease (MRD) in one subject. Three subjects that showed disease progression were treated with either alemtuzumab (1 subject) or ofatumumab plus high dose methylprednisolone therapy followed by allogeneic stem cell transplant (2 subjects). We observed clinical responses not only after FCR but also after infusion of Ad-ISF35-transduced cell. These ISF35-specific responses included reductions in absolute lymphocyte counts in all subjects (decrease from baseline 4–89%), and decreased lymphadenopathy (>50% reduction) in 78% of the subjects (decrease from baseline 19–100%). Infusion of Ad-ISF35-transduced cells plus FCR has been well-tolerated. The primary non-hematologic adverse events have been flu-like symptoms following infusion of Ad-ISF35 transduced cells. This includes transient grade I/II fever (89%), fatigue (56%) and chills (56%). The primary hematologic adverse events have been cytopenias following FCR treatment, including grade III/IV neutropenia (33%) and anemia (22%). Grade I/II hypophosphatemia (56%) following ISF35 has been observed and this might be related to increased serum cytokine levels following Ad-ISF35-transduced cell administration. Correlative studies on CLL cells obtained before and after infusions of Ad-ISF35-transduced CLL cells demonstrated that CLL cells prior to treatment were refractory to the cytoxic effects of P53-dependent drugs (e.g. F-ara-A). However, the CLL cells obtained after treatment with Ad-ISF35-transduced CLL had increases of p73, p21 and Bid and became sensitive in vitro to the cytotoxic activity of F-ara-A. We also observed up-regulation of costimulatory molecules (CD80, CD86, CD54) and death receptors (CD95). The majority of subjects developed antibodies against adenovirus with neutralizing activity. However, they did not developed antibodies against human CD154. Subjects also showed increases in TNFα, IL-6 and IL12 after infusion of Ad-ISF35 transduced cells. In conclusion, the combination of Ad-ISF35 transduced CLL cells plus FCR appears to be well-tolerated and highly effective in CLL patients with fludarabine-refractory disease and/or del(17p). The CR rate that we have observed in this high-risk CLL population is higher than those reported in the literature and makes our results very encouraging. Correlative data suggest that Ad-ISF35 promotes upregulation of costimulatory and death receptor molecules as well as pro-apoptotic proteins that may overcome resistance to FCR in vivo. These encouraging data suggest the combination of Ad-ISF35 plus chemoimmunotherapy could offer an effective treatment option for patients who otherwise would be resistant to standard forms of therapy. Disclosures: Cantwell: Memgen, LLC: Employment, Patents & Royalties.

Ad-ISF35-Transduced Autologous Cells Promote in Vitro and In Vivo Chemosensitization to FCR in Patients with Del(17p) / P53 Defective Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 376-376
Author(s):  
Januario E. Castro ◽  
Johanna Melo-Cardenas ◽  
Jose Sandoval-Sus ◽  
Mauricio Urquiza ◽  
Charles Prussak ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Cytotoxic Activity ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Agents ◽  
Whole Body ◽  
Multiparameter Flow Cytometry

Abstract Abstract 376 Chronic lymphocytic leukemia (CLL) cells that have del(17p) typically have loss of functional P53, rendering these cells refractory to standard chemotherapeutic agents, which require activation of P53 for their cytotoxic activity. However, del(17p) CLL cells co-cultured in vitro with cells transduced to express the CD40L (CD154) activate another member of the P53 family of proteins, namely P73, which, like P53, can induce transcription of death receptors and pro-apoptotic proteins and sensitize cells to the cytotoxic activity of “P53-dependent” drugs, such as Fludarabine (F-ara-A). Moreover, transduction of del(17p) CLL cells with a replication-defective adenovirus (Ad) encoding recombinant CD154 (Ad-ISF35) can induce such changes in both transduced and bystander CLL cells in vitro. To examine whether a similar activity could be obtained in vivo, we are conducting a phase Ib clinical study in subjects with high-risk CLL who are refractory to fludarabine or have evidence of del(17p). In this study, subjects receive three IV doses of 3×108 autologous CLL cells that had been transduced ex vivo with Ad-ISF35 and two weeks latter they are treated with a truncated chemoimmunotherapy regimen involving 3 monthly courses of fludarabine, cyclophosphamide and rituximab (FCR). P53-defective CLL cells from treated patients were initially resistant to F-ara-A induced apoptosis with IC50 > 10μM prior to treatment. CLL cells collected from patients ≥ 24 hours after the first infusion of autologous Ad ISF35-trasduced CLL cells became sensitive to the cytotoxic effects of F-ara-A, with IC50 0.3-1 μM. Enhanced sensitivity to F-ara-A was associated with induced expression of Bid, DR5, CD95, and P73 by circulating non-transduced “bystander” CLL cells, an effect lasting ≥ 2 weeks following IV infusion. To date, two subjects have completed treatment and this has been well tolerated without serious adverse events. The most common adverse events have been transient fever, malaise and fatigue associated to infusion of Ad-ISF35 transduced cells and cytopenias after treatment with FCR. Both subjects have achieved a compete response, one of them without detectable minimal residual disease (MRD) by sensitive multiparameter flow cytometry of marrow mononuclear cells obtained 3 months following completion of treatment. Moreover, these patients have complete resolution of lymphadenopathy and organomegaly by exam and by whole body computed tomography. These results indicate that Ad-ISF35-cell-gene therapy can sensitize P53-deficient CLL to “P53-dependent” cytotoxic agents in vivo, allowing for effective treatment of patients who otherwise would be resistant to standard forms of therapy. Disclosures: Prussak: Memgen: Employment.

Phase I Trial of Sphingosomal Vincristine (SV, Marqibo®) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4539-4539
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Leonard Heffner ◽  
Wendy Stock ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Dose Intensity ◽  
Complete Response ◽  
Antifungal Prophylaxis ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Pulse Dexamethasone

Abstract Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (Thomas et al., Cancer106:1641, 2006). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.

Immunoglobulin Heavy/Light Chain Measurements During Monitoring Provide Prognostic Information of Relapse After Therapy in Myeloma Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3964-3964 ◽  
Author(s):  
Mark T Drayson ◽  
Oscar Berlanga ◽  
Tim Plant ◽  
Nicola J Newnham ◽  
Philip Young ◽  
...  
Keyword(s):  
Partial Response ◽  
Light Chain ◽  
Progressive Disease ◽  
Residual Disease ◽  
Complete Response ◽  
Maximum Response ◽  
High Dose ◽  
Cell Transplant ◽  
Normal Ranges ◽  
Normal Ratio

Abstract Abstract 3964 Introduction: Monitoring multiple myeloma (MM) patients is required to help guide therapy and assess response. Currently the most commonly employed tests to monitor MM patients include serum protein electrophoresis (SPEP), immunofixation (IFE), 24hr urine and serum free light chain (FLC) analysis. Whilst electrophoretic tests are adequate for IgG MM, they may be inadequate for IgA MM where the monoclonal immunoglobulin co-migrates with other serum proteins (∼60% of cases). Recently the inclusion of FLC testing to identify patients in stringent complete response (sCR) has been recommended. Novel nephelometric reagents have become available that can quantify IgA kappa and IgA lambda immunoglobulins (HLC) in serum. Here we assess the use of these tests at maximum response to detect residual disease and comment on the prognostic value of sCR. Patients, materials and methods:196 IgA MM patient samples recruited from the MRC IX trial were assessed at maximum response. Briefly, patients were randomised on to intensive (I: induction therapy with CVAD or CTD followed by high-dose melphalan and ASCT) and non-intensive (NI: clodronate or zoledronic with MP or CTDa) arms. Median age was 59 years (range: 37–71) and 74 years (range: 65–89) for patients in the I and NI arms, respectively. 31% patients in the I arm and 39% in the NI arm presented with stage III disease. Samples were taken 3 months after autologous stem cell transplant or maximum response and analysed nephelometrically using serum FLC and HLC immunoassays. Ratios for both FLC and HLC were compared to normal ranges (FLC normal ratio= 0.256–1.65, IgAkappa/IgAlambda normal ratio=0.8–2.04). Additionally, isotype-matched immunoparesis was described as <0.48 g/L IgAkappa and <0.36g/L IgAlambda. Results were compared to SPEP, IFE and total immunoglobulin assays (where immunoparesis was described as <6g/L IgG and <0.4g/L IgM). 2-year progression free survival (PFS) was determined using Kaplan Meier analysis (SPSS v 19.0). Results: 3 months post-therapy, patient responses were: I arm: progressive disease (PD): n=1(<1%); minimal response (MR): n=1(<1%); partial response (PR): n=10(8%); very good partial response (VGPR): n=35(29%); complete response (CR): n=13(11%); sCR: n=58(48%); for two patients no data was available; NI arm: progressive disease (PD): n=3(4%); stable disease (SD): n=5(7%); MR: n=10(13%); PR: n=31(41%); VGPR: n=16(21%); CR: n=11(15%). Within the 2-year follow up, 41% patients in the I arm and 46% in the NI arm relapsed. Median PFS was not significantly different between the two arms (not reached v 7 months, p=0.65). Response (3VGPR) was not associated with PFS in either arm (I, p=0.717; NI, p=0.236). By contrast, achievement of a sCR (p=0.013) was significantly associated with longer PFS in the I arm and tended towards significance in the NI arm (p=0.063). An abnormal HLC ratio was associated with shorter PFS in both arms (I, p=0.002; NI, p=0.032). In all patients achieving a 3VGPR, an abnormal HLC ratio was associated with shorter PFS (p>0.0001). Similarly, in patients achieving a 3CR an abnormal HLC ratio was also associated with shorter PFS (p=0.04). Furthermore, patients achieving a CR where both FLC and HLC ratios were normal had a significantly longer PFS than those with an abnormal FLC or HLC ratio (median PFS not reached v 18 months, p=0.007). Isotype-matched immunoparesis was associated with shorter PFS in all patients achieving a CR (p=0.061). By contrast, systemic immunoparesis of either IgG or IgM immunoglobulins were not associated with PFS (p=0.525 and p=0.964, respectively). Discussion: Novel therapies have dramatically improved MM patient outcomes, however improvements in the assessment of those outcomes has not followed a similar trajectory. Here we present data suggesting immunoglobulin HLC ratios may be better markers of residual disease than electrophoretic methods. In addition a response category based on normalisation of both FLC and HLC ratios may be more valuable than sCR. Finally, the identification of isotype matched immune reconstitution as a marker of outcome suggests a preferential suppression of immunoglobulin production not previously reported. Conclusion: Normalisation of the FLC and HLC ratio at maximum response is a better assessment of disease than IFE. Further work is required to validate these results and to assess FLC and HLC ratios against multi-parametric flow cytometry. Disclosures: Young: Binding Site: Employment.

scholarly journals Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Blood ◽  
2019 ◽  
Vol 133 (26) ◽  
pp. 2765-2775 ◽  
Author(s):  
Ian W. Flinn ◽  
John G. Gribben ◽  
Martin J. S. Dyer ◽  
William Wierda ◽  
Michael B. Maris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Standard Dose ◽  
Tumor Lysis Syndrome ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

Abstract This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (&lt;10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

Eradication of Minimal Residual Disease Using Alemtuzumab Consolidation After High-Dose Methyl-Prednisolone Plus Rituximab (HDMP-R) Is Safe, Effective and Induces Long Term Remission in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2866-2866
Author(s):  
Januario E. Castro ◽  
Lina M. Ariza-Serrano ◽  
Juan S. Barajas-Gamboa ◽  
Julio A. Diaz-Perez ◽  
Danelle F. James ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Bulky Disease ◽  
Minimal Residual

Abstract Abstract 2866 Despite advances in the treatment of patients with chronic lymphocytic leukemia (CLL), the disease still remains incurable and eradication of minimal residual disease (MRD) being one of the most challenging goals of treatment. Alemtuzumab (Campath-H1™) has been shown to effectivily eradicate MRD from the bone marrow and induce long-term remissions, however its use is limited to patients without bulky disease. Futhermore, combination of alemtuzumab with chemotherapy has resulted in serious adverse events. In this study, we evaluate the toxicity and efficacy of alemtuzumab as consolidation therapy for CLL patients following induction with high-dose methylprednisolone in combination with rituximab (HDMP-R). Twenty-one patients with evidence of residual disease after treatment with HDMP-R received additional treatment with alemtuzumab. This antibody was administered three times a week for a total of 8 weeks. Patients received antibiotic prophylaxis with trimethoprim-sulfamethoxazole 160/800 mg twice a day × 3 per week, fluconazole 100 mg / day and valganciclovir 900 mg / day. The median age was 60 years (range, 49–73), with Rai stage III-IV in 81% of the patients. Twelve patients (57%) had evidence of unmutated IgVH gene and thirteen (62%) had high level of ZAP-70 expression. Cytogenetic and FISH analysis showed eight patients with deleletion 13q, three patients with trisomy 12, one patient with deletion 11q, five patients with no chromosomal abnomalities and in six patients data was not available. The median number of previous treatments was 1.3 (range, 0–5) and the median time from the end of HDMP-R treatment to initiation of alemtuzumab was 5 months (range, 1–14). After HDMP-R, nine patients (43%) achieved CR and twelve (57%) were in PR; all of them had evidence of residual disease in the bone marrow by 4-color flow cytometry analysis. Eight additional patients achieved CR after consolidation with alemtuzumab for a total of 17 patients (81%) in CR at the end of the study. We found no evidence of MRD (MRDneg) in 12 of those patients (57% of the total and 71% of CR patients). Of the remaining patients, one had PR and three patients had progressive disease for an overall response rate of 86%. The median progression-free survival (PFS) was 63 months (range, 6–84) for all patients. The median PFS in CR MRDneg patients has not been reached at a median follow-up of 46 months (range, 18–84), with 8/12 patients that have not progressed after a time at risk of 3.8 years. CR MRDpos patients have a median PFS of 48 months (range, 6–48). The treatment was well tolerated and there were no deaths attributed to therapy. Adverse events were classified following the NCI common terminology criteria for adverse events (CTCAE) Version 4.0. Two patients (9.5%) developed infections. The first event occurred during the administration of alemtuzumab and required hospitalization of the patient for management of pneumonia galactomannan positive suspicious for invasive aspergillosis (Grade 3), the second event was in a patient with aspegillus sp. infection of the skin that occurred four months after completion of alemtuzumab (Grade 2). Both patients recovered completely. We observed no CMV or other opportunistic infections. Three patients (14%) developed cytopenias; two patients with (Grade 4) thrombocytopenia and three patients with (Grade 4) neutropenia. In conclusion, alemtuzumab consolidation for residual disease after treatment with HDMP-R was well tolerated and effective in patients with CLL. We observed a near two-fold increase in the number of patients that achieved CR and the majority of these (71%) had no evidence of MRD. Moreover, patients with CR MRDneg have an exceptionally long PFS. The low rate of infection and lack of treatment related mortality compares very favorably with previous studies using alemtuzumab consolidation after chemotherapy treatment in which toxicities including treatment related death were found to be prohibitive. These encouraging results provide the rationale for additional studies using this combination therapy. Disclosures: James: Celgene: Research Funding.

scholarly journals A Multicenter Phase II Study Evaluating Fludarabine, Cyclophosphamide, and Subcutaneous Campath (FCCAM) for Previously Untreated Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5667-5667
Author(s):  
Steven E. Coutre ◽  
Chadi Nabhan
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Standard Dose ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Weekly Schedule ◽  
Multicenter Phase

BACKGROUND: Chemoimmunotherapy for chronic lymphocytic leukemia (CLL) has been the standard of care for initial treatment. A randomized demonstrated both a progression free survival (PFS) and overall survival (OS) advantage when rituximab was added to fludarabine (F) and cyclophosphamide (C). Alemtuzumab (Campath) (CAM), an anti-CD52 monoclonal antibody, is an effective therapy for patients with both previously untreated and relapsed CLL. Its role in combination with chemotherapy is less certain. METHODS: We conducted a multicenter phase II clinical trial of FC followed by subcutaneous CAM in previously untreated CLL. Patients were eligible if they met standard criteria for initiating therapy, or if they were asymptomatic with the prognostically adverse immunoglobulin heavy chain variable (IGHV) gene unmutated status. Patients received fludarabine (25 mg/m2/day, days 1-3) and cyclophosphamide (250 mg/m2/day, days 1-3) every 28 days for six treatment cycles, followed by a 3-8 week rest period. Disease response was assessed, including minimal residual disease (MRD) status by sensitive flow cytometry in those in complete remission (CR). Patients who achieved less than a CR were eligible to receive standard dose CAM (30 mg thrice weekly for 12 weeks); those who were in CR but MRD positive could receive reduced dose CAM (30 mg weekly for 12 weeks). The primary outcome was duration of response (DOR). Secondary outcomes included the response rates after FC and after the addition of CAM, as well as the safety profile of the regimen. RESULTS: We enrolled 25 patients from November 2004 to June 2007 at 3 centers. The median age of the participants was 62 years (range 42-75). Detailed information was available for 17 patients pre-treatment: high risk Rai stage in 9, IGHV unmutated in 9 including 4 patients who were IGHV unmutated as their indication for treatment. Five patients had trisomy 12, 4 had 13q deletion, 1 each had 17p deletion and 11q deletion, and 6 had no abnormality. One patient was excluded from the analysis due to a diagnosis of mantle cell lymphoma after eligibility review. Four patients had no response evaluation and were considered treatment failures. Seventeen (71%) patients had a CR after 6 cycles of FC, including 11 who were MRD negative, one had a partial response (PR), and two had progressive disease (PD). Four of the 6 patients who were MRD positive received CAM after FC. Two required only a single dose to become MRD negative, and 2 received 12 weekly doses. One of these patients became MRD negative. The median DOR for those achieving CR was 38 months (range 12-105 months). There were no treatment related deaths. Five patients experienced a SAE including one with febrile neutropenia, two with pneumonia, and two with autoimmune hemolytic anemia. There were ten additional treatment emergent adverse events including two that were grade 3 (mucositis and fever) and one CMV reactivation while receiving CAM. Two patients developed treatment related myelodysplasia, one died and the other underwent allogeneic stem cell transplant. There were two deaths due to Richter’s transformation. During long term follow up, there have been five additional deaths. CONCLUSIONS: The CR rate after FC was higher than that reported in prior trials of previously untreated patients and the incidence of MRD negative CR was surprisingly high. The DOR was consistent with prior experience with FC. Too few patients received CAM to draw any conclusions about its role as a consolidative therapy given subcutaneously on a weekly schedule. Both the FC and CAM therapies were well tolerated, with few adverse events associated with their use. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sequential Therapy With Fludarabine, High-Dose Cyclophosphamide, and Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia Produces High-Quality Responses: Molecular Remissions Predict for Durable Complete Responses

2009 ◽  
Vol 27 (4) ◽  
pp. 491-497 ◽  
Author(s):  
Nicole Lamanna ◽  
Joseph G. Jurcic ◽  
Ariela Noy ◽  
Peter Maslak ◽  
Alison N. Gencarelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Response Duration ◽  
Sequential Therapy ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Entire Group ◽  
High Dose ◽  
Safe Delivery ◽  
Negative State

Purpose Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F→C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F→C→R). Patients and Methods Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m2 on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m2 administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m2 for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgVH genes. Results There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F→C regimen (P = .10). Conclusion Sequential therapy with F→C→R yields improvement in quality of response, with many patients achieving a PCR-negative state.

scholarly journals Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN

2021 ◽  
Vol 5 (4) ◽  
pp. 1092-1096
Author(s):  
Peter M. Voorhees ◽  
Cesar Rodriguez ◽  
Brandi Reeves ◽  
Nitya Nathwani ◽  
Luciano J. Costa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Survival Rates ◽  
Final Analysis ◽  
Complete Response ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Best Response

Abstract The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With &gt;3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

scholarly journals Ibrutinib plus obinutuzumab as frontline therapy for chronic lymphocytic leukemia is associated with a lower rate of infusion-related reactions and with sustained remissions after ibrutinib discontinuation: a single-arm, open-label, phase 1b/2 clinical trial NCT0231576

2021 ◽  
Author(s):  
Januario E. Castro ◽  
Paula A. Lengerke-Diaz ◽  
Juliana Velez-Lujan ◽  
Michale Y. Choi ◽  
Eider F. Moreno-Cortes ◽  
...  
Keyword(s):  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Continuous Administration ◽  
Open Label Phase ◽  
Phase 1B ◽  
Treatment Safety ◽  
Anti Cd20

Abstract Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials.

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8004-8004
Author(s):  
Philippe Moreau ◽  
Pieter Sonneveld ◽  
Keyword(s):  
Interim Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Second Primary ◽  
Cell Transplant ◽  
Open Label ◽  
Depth Of Response

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P <0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P< 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P <0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P <0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

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