The Chemotherapy Regimen IVAC Is Highly Active for Multiply Relapsed and Refractory Hodgkin Lymphoma

Abstract Abstract 4863 Background: Hodgkin Lymphoma (HL) has a cure rate of 70% with chemotherapy or combined modality therapy. Despite this success, approximately 5–10% of patients have primary refractory disease, and 20–30% of patients will relapse after initial complete remission (CR). Second-line chemotherapy and autologous stem cell transplant (ASCT) approaches are curative for only 50% of patients with relapsed/refractory disease. Maximal cytoreduction prior to ASCT confers the greatest potential benefit, yet the current standard salvage chemotherapy regimens have a low CR rate despite a high overall response rate (ORR), and survival is poor for patients who relapse after ASCT. Allogeneic stem cell transplantation can induce durable remissions in some patients with relapsed and primary refractory HL; however the use of this modality is limited in part by the challenges of achieving adequate disease control prior to transplantation. Novel treatment platforms to maximally debulk these patients and allow them to proceed to successful transplantation are needed. Our group has treated multiply relapsed HL patients with the chemotherapy regimen of Ifosfamide, Etoposide, and Cytarabine (IVAC) and we report a retrospective chart review detailing our experience. Methods: Between January of 2011 and June of 2012, 4 patients with relapsed or primary refractory HL were treated with the chemotherapy regimen IVAC consisting of: Ifosfamide 1,500mg/m2 days 1–5; MESNA 1,500mg/m2 days 1–5, Etoposide 600mg/m2 days 1–5, and Cytarabine 2,000mg/m2 q 12hrs × 4 doses days 1–2 given every 21 days. All patients received growth factor support beginning 24hrs after completion of chemotherapy. All patients received prophylactic antifungal, antiviral, and PCP prophylaxis. Restaging PET/CT was performed after 2 cycles of therapy. All patients received 2 cycles of therapy prior to assessment for transplant. Results: Four patients have been treated to date on this regimen. The mean age of the 4 patients was 35.5 (range 32–43). All patients were male. All patients were heavily pre-treated with a mean of 8 prior chemotherapy regimens (range 7–9) including ICE (Ifosfamide, Carboplatin, Etoposide) and Brentuximab vedotin. Three of the 4 patients had prior stem cell transplant: autologous (n=2), allogneic with subsequent DLI (n=1). All patients tolerated the chemotherapy well. The most common significant adverse events were: grade 3 pneumonia (1/4 patient), grade 3 febrile neutropenia (1/4 patients), grade 3 neutropenia (4/4 patients), grade 3 anemia (4/4 patients), grade 3 thrombocytopenia (4/4 patients). All patients recovered to baseline before initiating cycle 2, and after the completion of therapy. Response was evaluated after 2 cycles of therapy in all patients. Three of 4 patients (75%) had a response giving an ORR rate of 75%. Two of the 3 responding patients had a CR giving a CR rate of 50%, 1 patient had a PR. Response duration was: 6 weeks (n=1), 3 months (n=1), 6 months (n=1). Conclusion: IVAC is highly active, even in heavily pre-treated HL patients, with an ORR of 75% and a CR rate of 50%. With close clinical monitoring hematologic and infectious toxicities were manageable in all patients. The regimen of IVAC may allow disease debulking for multiply relapsed HL patients prior to stem cell transplant. Prospective evaluation of this therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.

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Bendamustine Is Highly Active in Heavily Pre-Treated Relapsed and Refractory Hodgkin Lymphoma and Serves as a Bridge to Allogeneic Stem Cell Transplant.

Blood ◽

10.1182/blood.v114.22.720.720 ◽

2009 ◽

Vol 114 (22) ◽

pp. 720-720 ◽

Cited By ~ 11

Author(s):

Alison J. Moskowitz ◽

Paul A. Hamlin ◽

John Gerecitano ◽

Steven M. Horwitz ◽

Matthew Matasar ◽

...

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Stem Cell Transplant ◽

Single Agent ◽

Maximal Response ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Treatment Delays ◽

Highly Active ◽

Grade 3

Abstract Abstract 720 Introduction: No standard treatment exists for relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) failure and prognosis is poor. Nonmyeloablative allogeneic stem cell transplant (NMT) offers a chance of cure in a subset of these patients; therefore the goal of treatment should be to ultimately refer patients to NMT. Bendamustine is a bifunctional alkylating agent, recently FDA approved for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Limited data supports the use of bendamustine in HL (Borchmann, et al. Ann Oncol 1998). Methods: This is a phase II clinical trial evaluating the activity of single-agent bendamustine in rel/ref HL for ASCT failures, NMT failures, or patients (pts) who are ineligible for transplant. Our primary outcomes are response rate and, for eligible pts, referral to NMT. Pts receive bendamustine 120mg/m2, for two consecutive days, every 28 days. Pegfilgrastim is administered with each cycle and treatment is delayed until absolute neutrophil count is > 1000/ul and the platelet count is > 75,000/ul. Dose is reduced to 100mg/m2 in cases of treatment delays > 5 days due to neutropenia or thrombocytopenia or for grade 3 non-hematologic toxicities. Pts are evaluated for response by CT and PET after 2, 4, and 6 cycles. Pts deemed eligible for NMT at initiation of bendamustine are referred when they have had maximal response to bendamustine. Others receive a maximum of 6 cycles. Results: To date, 18 out of a planned 37 pts have been enrolled. Twelve of the 18 pts previously failed ASCT, 2 failed NMT. Of 16 evaluable pts, 2 progressed prior to the first re-evaluation and died rapidly from HL. Of the remaining 14 pts, 12 pts responded. There were 6 CRs (38%), 6 PRs (38%), 1 SD; ORR was 75%. All responding pts showed evidence of improvement at first restaging. One pt withdrew consent after 1 cycle. This pt achieved a CR and has been monitored off therapy for 10 months. At time of enrollment, 12 of the 16 evaluable pts were deemed eligible for NMT. Reasons for NMT ineligibility were additional comorbidities (3) and previous NMT (1). Of the 12 NMT eligible pts, 3 have completed NMT and 3 were referred but ultimately refused. The three completed NMTs were performed following 4 cycles of bendamustine. Bendamustine was very well tolerated. Three SAEs have occurred: grade 3 nausea following cycle 1, fungal pneumonia following cycle 2, and pyelonephritis following cycle 6. There have been 6 treatment delays due to thrombocytopenia (3), neutropenia (1), pneumonia (2). There have been 4 treatment reductions due to neutropenia (2), nausea (1), and thrombocytopenia (1). Conclusion: Interim results from this ongoing trial indicate that bendamustine is highly active in heavily pre-treated rel/ref HL and enables referral to NMT in a significant portion of eligible pts. Future studies will combine bendamustine with novel agents in rel/ref HL. Disclosures: No relevant conflicts of interest to declare.

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Characteristics and Outcome of Patients with Acute Myeloid Leukemia (AML) Refractory to One Cycle of High Dose Cytarabine-Based Induction Chemotherapy.

Blood ◽

10.1182/blood.v114.22.1038.1038 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1038-1038

Author(s):

Farhad Ravandi ◽

Jorge Cortes ◽

Stefan Faderl ◽

Susan O'Brien ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplant ◽

Conflicts Of Interest ◽

Single Agent ◽

Salvage Chemotherapy ◽

High Dose ◽

Cell Transplant ◽

Refractory Disease ◽

Allogeneic Stem Cell Transplant

Abstract Abstract 1038 Poster Board I-60 Background: Outcome of patients (pts) with AML refractory to initial induction is assumed to be poor but the available data is limited. Furthermore, pts refractory to standard dose cytarabine-based regimens may be salvaged with high dose ara-C (HiDaC, defined as daily ara-C dose ≥ 1 g/m2). Information on the outcome of pts refractory to initial HiDaC - based induction is more limited. Aim To better characterize predictors of poor response to HiDaC-based induction and to evaluate the outcome of pts refractory to such induction regimens. Methods: We identified pts treated with induction regimens containing HiDaC at the University of Texas – M D Anderson Cancer Center who did not achieve a compete remission (CR) after one cycle of induction. We examined their pre-treatment characteristics and compared them with similar pts achieving a CR. We also examined their response to salvage chemotherapy and outcome. Results: Among 1179 pts treated with HiDaC-based induction therapy from 1995 to 2009, 285 were primary refractory to one course of induction. Their median age was 59 (range, 18 - 85). Median pretreatment WBC was 9.0 × 109/L (range, 0.3 – 394 × 109/L). Cytogenetics included-5/-7/complex 101 (35%), diploid 85 (30%), other intermediate 98 (34%), favorable 1 (<1%). 165 (58%) pts had antecedent hematological disorder. Induction regimens used included HiDaC with anthracyclines (n=181, 64%), HiDaC with non-anthracycline chemotherapy (fludarabine, clofarabine, topotecan, and troxacitabine) (n=104, 36%) Pts with primary refractory disease were older (Median age 59 vs. 56; p=000004), more likely to have chromosome 5/7 or complex cytogenetic abnormalities (P=0.0001), more likely to have AHD (p=0.0001), and had a higher presentation WBC (P=0.036), but not a higher incidence of FLT3 mutations (p=0.85) than those achieving CR. Primary refractory disease was not more likely with non-anthracycline containing regimens than those with anthracyclines (p=0.58). Salvage chemotherapy included combination chemotherapy in 111 (39%)(non-ara-C regimen in 40, containing ara-C in 71), single agent chemotherapy in 64 (22%), allogeneic stem cell transplant in 22 (8%) and none in 88 (31%). Forty-three (15%) pts responded to salvage including 35 CR and 8 CRp. 114 (58%) pts were resistant and 35 (18%) died; 5 (3%) were lost to follow-up. With a median follow-up of 115 weeks (range 8 – 347 weeks) in pts responding to salvage, 21 pts (7%) were alive and in CR, for at least 6 months including 14 who underwent an allogeneic stem cell transplant (median overall survival for these 21 pts, 30 months; range, 13 to 87 months). Conclusions: Outcome of pts with disease refractory to HiDaC-based induction is poor. Alternative strategies are needed in these pts who are likely to be resistant to standard chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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FDG-PET Adapted Sequential Therapy With Brentuximab Vedotin and Augmented ICE Followed By Autologous Stem Cell Transplant For Relapsed and Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.2099.2099 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2099-2099 ◽

Cited By ~ 5

Author(s):

Alison Moskowitz ◽

Heiko Schoder ◽

John F. Gerecitano ◽

Paul Hamlin ◽

Steven M. Horwitz ◽

...

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Salvage Therapy ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Genetics Research ◽

Grade 3

Abstract Background Pre-transplant FDG-PET (PET) normalization is the strongest predictor of outcome following autologous stem cell transplant (ASCT) for patients with relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) (Moskowitz, AJ. Blood. 2010 Dec 2;116(23):4934-7). Due to its high efficacy in ASCT failures, we aimed to determine whether brentuximab vedotin (BV) can replace ICE (ifosfamide, carboplatin, etoposide) salvage therapy, increase rate of PET normalization, and enhance referral to ASCT for patients (pts) who fail front-line HL therapy. Here we present our phase II study evaluating a novel salvage strategy for rel/ref HL, an intent-to-treat study of PET-adapted sequential therapy with BV and augmented ICE (augICE) prior to ASCT. Methods Patients with rel/ref HL who have failed 1 prior regimen are enrolling on this phase II clinical trial. Patients receive weekly brentuximab vedotin (BV) administered at 1.2mg/Kg IV weekly for 3 weeks on and 1 week off for 2 cycles, followed by PET. Patients who achieve normalization of PET (Deauville 2 or less) proceed to ASCT. Patients with PET scores of Deauville 3 or higher receive 2 cycles of augICE prior to consideration for ASCT. Results 41 of planned 46 patients have enrolled; 34 pts completed salvage therapy, of whom 33 proceeded to ASCT. 28 pts are at least 90 days post-ASCT and represent the focus of this report. These 28 pts include 20 (71%) males, 21 (75%) pts with primary refractory or relapse within 1 year of initial treatment, 11 (39%) with B symptoms at enrollment and 11 (39%) with extranodal disease. Median number CD34+ cells/kg collected were 7.44x 10^6 (2.96 - 31.43x10^6). Disease status prior to ASCT was CR (Deauville 2) for 27 pts and PR (Deauville 3) for 1 pt. Salvage therapy for pts in CR prior to ASCT include BV alone (9), BV followed by augICE (16), and BV followed by augICE (with Deauville 4 response) followed by involved field radiation to achieve CR (2). The 1 patient in PR prior to ASCT received BV followed by augICE. Conditioning regimens included BEAM (9), CBV( 9), and high dose chemoradiotherapy (10). Early (within 90 days) transplant-related toxicities include grade 2 pneumonitis (3pts) and grade 3 acute kidney injury (1pt); late toxicities include grade 3 esophageal stenosis (1pt), grade 3 acute kidney injury (1pt), and 1 death (7 months post ASCT) due to progressive multifocal leukoencephalopathy. After a median follow-up of 9.5 months post-ASCT (range 3.3-15.6 months), 2 of 28 pts have progressed (at 2.7 and 4.3 months post ASCT respectively). One achieved a second CR with BV and proceeded to allogeneic stem cell transplant (alloSCT); the second achieved near CR following GND (gemcitabine, vinorelbine, Doxil) and proceeded to alloSCT. Conclusion PET-adapted sequential salvage therapy with BV followed by augICE produces high CR rates, adequate stem cell collection, and facilitates referral to ASCT for virtually all pts. Updated results will be presented at the meeting. Disclosures: Moskowitz: Seattle Genetics: Research Funding. Off Label Use: Brentuximab vedotin is approved for treatment of Hodgkin lymphoma following failure of 2 multi-agent regimens or autologous stem cell transplant. This study is evaluating the use of brentuximab vedotin in the pre-transplant setting for Hodgkin lymphoma. Schoder:Seattle Genetics: Research Funding. Hamlin:Seattle Genetics : Consultancy, Honoraria. Horwitz:Millennium: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Moskowitz:Seattle Genetics: Research Funding.

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A phase II study of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7576 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7576-7576 ◽

Cited By ~ 5

Author(s):

K. A. Blum ◽

J. L. Johnson ◽

D. Niedzwiecki ◽

G. P. Cannellos ◽

B. D. Cheson ◽

...

Keyword(s):

Stem Cell ◽

Disease Progression ◽

Hodgkin Lymphoma ◽

Cell Lines ◽

Phase Ii ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Motor Neuropathy ◽

Bleeding Gastric Ulcer ◽

Grade 3

7576 Background: Constitutive NF-κB activation has been described in both Hodgkin lymphoma (HL) cell lines and patient-derived Reed-Sternberg cells. In vitro, therapeutic targeting of NF-κB with proteasome inhibitors like bortezomib leads to apoptosis of HL cell lines, providing a rationale for clinical trials with this agent. Methods: From 3/15/2004 until 2/23/2005, the CALGB conducted a phase II trial of bortezomib in patients (pts) with relapsed and refractory classical HL to assess response rate and toxicity. Eligibility requirements included at least one prior systemic therapy, measurable disease, absolute neutrophil count ≥ 750/μL, platelets ≥ 75,000/μl, and creatinine ≤ 2.5 mg/dl. Pts able to undergo a stem cell transplant with curative intent or with pre-existing sensory neuropathy ≥ grade 2 were not eligible. Bortezomib was administered at 1.3 mg/m2 days 1, 4, 8, and 11 every 21 days for 2–8 cycles, or until disease progression. Results: 30 pts received a median of 2 cycles (range, 1–8). For 25 pts with available data, 80% had stage IV disease with a median of 4 prior therapies (range 2–8, 92% with prior stem cell transplant). For 29 pts with complete response data, 2 pts were not evaluable due to adverse events (bleeding gastric ulcer and grade 4 dyspnea) during cycle 1 leading to a discontinuation of therapy prior to restaging. In the remaining 27, no responses were observed [95% CI (0.0, 0.13)]; 18 pts progressed, and 9 pts had stable disease. Median follow-up is 4.4 (range, 0.6 -16.4) months. The median progression-free and overall survival times are 1.4 [95% CI (1.3, 2.8)] and 11.6 months [95% CI (6.6, ongoing)], respectively. Toxicity data are available for 26 pts. Grade 3–4 events included thrombocytopenia (27%), lymphopenia (8%), dyspnea (8%), anemia (4%), diarrhea (4%), hypotension (4%), rash (4%), and hyperbilirubinemia (4%). Both instances of grade 3–4 dyspnea occurred in pts with disease progression in the lung. 27% developed grade 2 sensory or motor neuropathy. Conclusions: Although well-tolerated, bortezomib has no single agent efficacy in relapsed classical HL at the current dose and schedule. No significant financial relationships to disclose.

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