scholarly journals A Latin-American Cancer Center Experience in the Treatment of Hodgkin's Lymphoma during a Drug Shortage

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1919-1919
Author(s):  
Luis Felipe Felipe Rubalcava ◽  
Gabriela Cesarman-Maus ◽  
Ana Florencia Ramirez-Ibarguen
Keyword(s):  
Latin American ◽  
Hodgkin’S Lymphoma ◽  
Response Rate ◽  
Response Rates ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Drug Shortage ◽  
Histologic Subtype ◽  
Chemotherapy Protocol ◽  
One Year

Abstract The treatment of Hodgkin's lymphoma has been characterized by a story of success with the use tried-and-true protocols. During the second half of 2019 to the first-half of the 2021 the Mexican health system experienced a shortage of drugs, which compromised the possibility of using in most of the common protocols for this cancer: ABVD, BEACOPP, IGEV, ESHAP, DHAP, GEMOX. Clinician had option of using a common protocol with incomplete doses or applying an alternative complete CHOEP protocol, which has been used with some success in exploratory studies [1,2]. For 12 months, we treated a total of 58 patients of which we compared the base characteristics and response rates to 10-year compiled data from pre-shortage patients (PS) (total 475). The baseline characteristics of the PS vs shortage (S) group showed a statistical similar gender distribution (males 55.2% vs 63.8%, P 0.21), histologic subtype (P 0.24), international prognostic score (IPS ≥3 57.7% vs 58.6%, P 0.89) and clinical stage (advanced 78.1% vs 84.5%, P 0.26). The S patients did show higher frequency of B symptoms (P 0.002), extranodal disease (P 0.0001), while the PS group had a higher frequency of bulky disease (P 0.001), ABVD protocol (96% vs 63.8%, P 0.0001) and radiotherapy use. In the S group a total of 37 ABVD (29 incomplete), 7 BEACOPP (5 incomplete) and 14 CHOEP protocols (1 incomplete) were infused, it means only 10 (17.7%) were able to receive a standard complete treatment, while the rest received an incomplete or alternative treatment. Complete response for the PS and S group were 71.4% vs 56.9% with the corresponding therapeutic failure 28.6% vs 43.1% (p 0.023) respectively. Analyzing the response rate of each chemotherapy protocol in the S group, the complete ABVD vs incomplete ABVD demonstrated an 87.5% vs 69% (p 0.28) respectively. The complete BEACOPP vs incomplete showed 50% vs 40% (p 0.7) and CHOEP exhibited an unexceptional complete response rate of 21.4%. The median follow up was 48 months (1-148) for all cohort. One year OS were 98% vs 82% on PS vs S group respectively (log rank 0.0001). One year-PFS for the PS and S group were 96% and 61% respectively (log rank 0.003). The risk factors associated with lower PFS were B symptoms (OR 1.7, 1.1-2.6), advanced disease (OR 1.66, 1-0-2.7) and IPS≥3 (OR 2.1, 1.4-3.3); as favorable factors we observed radiotherapy (OR 0.07, 0.6-0.8) and the PS group (OR 0.5, 0.3-1.0); however, in the Cox regression, only the IPS≥3 remained as an independent unfavorable factor (HR 1.8, 1.2-2.6), as did radiotherapy (HR 0.4, 0.3-0.6) as favorable. For the OS the drug shortage were an independent risk factor (HR 2.2, 1.1-4.3) like IPS ≥3 (HR 2.8, 1.5-5.1). Analyzing the 1-year PFS in the S group according to which chemotherapy protocol they received, those with ABVD or BEACOPP (regardless of the complete dose status) was of 72%, compared to 20% (P 0.001) in the CHOEP regimen. CHOEP regimen in LH patients is ineffective treatment. In times of shortages, continuing with incomplete standard schemes offers better response rates than alternative schemes. Despite Hodgkin's lymphoma is considered a neoplasm with high cure rates when an economic recession followed by an international event (for example a global pandemic) limited our availability for the use of standard treatments, an area of opportunity for considering alternative protocols has risen for resource-limited countries and institutions. [1] Walewski J,et al. CHOP-21 for unfavorable Hodgkin's lymphoma. An exploratory study. Med Oncol. 2010;27(2):262-7 [2] Kolstad A, et al. Standard CHOP-21 as first line therapy for elderly patients with Hodgkin's lymphoma. Leuk Lymphoma. 2007;48(3):570-6 Disclosures No relevant conflicts of interest to declare.

ABVD Versus Modified Stanford V Versus MOPPEBVCAD With Optional and Limited Radiotherapy in Intermediate- and Advanced-Stage Hodgkin's Lymphoma: Final Results of a Multicenter Randomized Trial by the Intergruppo Italiano Linfomi

2005 ◽  
Vol 23 (36) ◽  
pp. 9198-9207 ◽  
Author(s):  
Paolo G. Gobbi ◽  
Alessandro Levis ◽  
Teodoro Chisesi ◽  
Chiara Broglia ◽  
Umberto Vitolo ◽  
...  
Keyword(s):  
Adjuvant Radiotherapy ◽  
Hodgkin’S Lymphoma ◽  
Response Rate ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Free Survival ◽  
Drug Doses ◽  
Advanced Hodgkin’S Lymphoma

Purpose In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to ≤ two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). Patients and Methods Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. Results The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. Conclusion When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

2-Chlorodeoxyadenosine is an active salvage therapy in advanced indolent non-Hodgkin's lymphoma.

1994 ◽  
Vol 12 (4) ◽  
pp. 788-792 ◽  
Author(s):  
M Hoffman ◽  
M S Tallman ◽  
D Hakimian ◽  
D Janson ◽  
D Hogan ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Hodgkin’S Lymphoma ◽  
Response Rate ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Chemotherapy Drugs ◽  
Non Hodgkin’S Lymphoma ◽  
Major Toxicity ◽  
Non Hodgkin's Lymphoma ◽  
Pretreated Patients

PURPOSE To determine the response rate to 2-chlorodeoxyadenosine (2-CdA; cladribine) in patients with advanced indolent non-Hodgkin's lymphoma (NHL) who fail to respond to or progress after a response to standard chemotherapy drugs. PATIENTS AND METHODS Twenty-one patients were treated with at least one cycle of 2-CdA 0.1 mg/kg/d by continuous infusion for 5 or 7 days. RESULTS The overall response rate (complete response [CR] and partial response [PR]) was nine of 21 patients (43%; 95% confidence interval, 22% to 64%). Unmaintained durable responses (longest follow-up, 29+ months) have been observed. The treatment was well tolerated by all patients. The major toxicity was related to myelosuppression (predominantly neutropenia) and immunosuppression with infection. CONCLUSION The purine analog 2-CdA is an active salvage therapy in pretreated patients with indolent NHL, and deserves further assessment in untreated patients and in combination with other chemotherapy agents.

Results of Multicentre Phase IV Study of Rituximab in Combination with CHOP Chemotherapy in Patients with Previously Untreated Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4624-4624
Author(s):  
Ti Shen ◽  
Zhongzhen Guan ◽  
Zhixiang Shen ◽  
Yuankai She ◽  
Jun Zhu
Keyword(s):  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Response Rate ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Newly Diagnosed ◽  
Chop Chemotherapy ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Phase Iv

Abstract Purpose: Rituximab is a chimeric anti-CD20 monoclonal antibody that was the first antibody approved by the FDA in the United States of America and SDA in China for the treatment of B-cell non-Hodgkin’s Lymphoma (NHL). It has shown significant efficacy and good tolerability in refractory and relapsed NHL. We have conducted a multicenter phase IV trial to evaluate the efficacy and safety of rituximab combined with standard CHOP chemotherapy in patients with newly diagnosed B-NHL. Methods: Patients with newly diagnosed, histologically proven CD20-positive NHL were eligible for the study. All patients received 4–6 infusions of rituximab (375mg/m2 per dose) in combination with CHOP chemotherapy, either concurrently (rituximab administered on the first day of each 21-day CHOP cycle) or sequentially (4–6 once-weekly infusions of rituximab followed by six 21-day cycles of CHOP). Each CHOP cycle consisted of cyclophosphamide 750 mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (maximum 2.0mg/dose) given intravenously on day 1, and prednisone 100mg/day orally on days 1-5. Tumor responses were assessed at the end of treatment. Results: A total of 347 patients were recruited between February 2002 and December 2003. Of these 235 (68%) were male and 94 (27%) aged >60. The main lymphoma subtypes were diffuse large B-cell 196 (56%), follicular 41(12%), small lymphocytic/chronic lymphocytic leukemia 13(4%) and MALT 11(3%). Ann Arbor staging was as follows: stage I, 52 (15%); stage II, 80 (23%); stage III, 90(26%); stage IV, 105(30%); twenty patients (6%) could not be assessed. Of the 347 patients enrolled, 314 were evaluable for response. An objective response was observed in 94% of evaluable patients with a complete response (CR) in 56%, stable disease in 3.8% and progressive disease in 2.5%. The complete response rate was 63% for patients receiving 6 cycles of rituximab and 54% for those receiving four cycles of rituximab. No difference in response rate was observed between the sequential and concurrent groups. The most common adverse events were leucopenia in 122 patients (35%), nausea and vomiting 66 (19%), fever 39 (11%), rash 15 (4%) and asthma 4 (1%). Conclusion: The combination of rituximab and CHOP chemotherapy is an effective and well-tolerated treatment for patients with newly-diagnosed CD20-positive NHL. The safety and efficacy achieved in this study suggests that more than four doses of rituximab may be required for optimal efficacy.

Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma.

1987 ◽  
Vol 5 (9) ◽  
pp. 1329-1339 ◽  
Author(s):  
M J O'Connell ◽  
D P Harrington ◽  
J D Earle ◽  
G J Johnson ◽  
J H Glick ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hodgkin’S Lymphoma ◽  
Eastern Cooperative Oncology Group ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Histologic Subtype ◽  
Non Hodgkin’S Lymphoma ◽  
Frequent Administration ◽  
Non Hodgkin's Lymphoma ◽  
Ann Arbor

Three hundred thirty-two eligible patients with advanced (Ann Arbor stage III or IV) non-Hodgkin's lymphoma of aggressive histologic subtype (Rappaport classification diffuse histiocytic [DH], diffuse poorly differentiated lymphocytic [DPDL], diffuse mixed [DM], or diffuse undifferentiated [DU]) were randomly assigned to receive induction chemotherapy with one of three intensive regimens in a clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) between 1978 and 1983. Chemotherapy regimens consisted of cyclophosphamide, vincristine, prednisone, and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (COPA) administered in 3-week cycles; cyclophosphamide plus doxorubicin plus prednisone beginning day 1, with vincristine plus bleomycin day 15 of each 3-week cycle (COPA + Bleo); or cyclophosphamide plus doxorubicin plus procarbazine beginning day 1, and bleomycin plus vincristine plus prednisone beginning day 15 of each 4-week cycle (CAP-BOP). The median patient follow-up from study entry for patients still alive is 5 years. The three regimens were not significantly different with respect to complete response (CR) rates (43% to 46%), time to progression of malignant disease (median, 1.0 to 1.7 years), or survival (5-year survival, 34% to 45%), although duration of complete remission appeared to be shorter in patients receiving COPA (P = .03). COPA + Bleo and CAP-BOP were significantly more toxic than the COPA regimen. This study did not demonstrate any substantial therapeutic advantage associated with the addition of a fifth or sixth chemotherapy drug, or with treatment administered on a more frequent administration schedule, compared with the COPA regimen in this population of patients with advanced diffuse non-Hodgkin's lymphoma. The relatively small proportion of long-term disease-free survivors treated with COPA underscores the need for prospective clinical trials of new and more effective treatments for patients with these potentially curable tumors.

Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

1994 ◽  
Vol 12 (4) ◽  
pp. 769-778 ◽  
Author(s):  
I A Cooper ◽  
M M Wolf ◽  
T I Robertson ◽  
R M Fox ◽  
J P Matthews ◽  
...  
Keyword(s):  
New Zealand ◽  
Hodgkin’S Lymphoma ◽  
Response Rates ◽  
Large Cell ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Intermediate Grade ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Significant Difference

PURPOSE To compare complete response rates, time to failure, survival, and toxicity for patients with intermediate-grade non-Hodgkin's lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) versus those treated with a regimen consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B), in a multicenter, randomized controlled trial performed by 22 centers of the Australian and New Zealand Lymphoma Group (ANZLG). PATIENTS AND METHODS Between October 1986 and June 1991, 304 patients were randomized, of whom 236 were eligible for analysis. Eligibility criteria included diffuse small cleaved-cell, diffuse mixed small- and large-cell, follicular large-cell, diffuse large-cell, and large-cell immunoblastic, stages I bulky or II to IV. RESULTS There was no significant difference in complete response rates (51% for MACOP-B v 59% for CHOP), failure-free survival, or overall survival in the two treatment arms. The rate of death of MACOP-B patients relative to CHOP patients was estimated to be 0.91 (P = .64) when stratified by prognostic group. There were no significant differences between the two regimens in any of the prognostic subgroups. Toxicity was significantly more severe with MACOP-B, particularly cutaneous toxicity, stomatitis, and gastrointestinal ulceration. The average relative dose-intensity (RDI) of MACOP-B was 0.91 and of CHOP was 0.90, indicating good dose delivery in this multicenter group setting. CONCLUSION CHOP chemotherapy produced results equivalent to those of MACOP-B in patients with intermediate-grade NHL and with significantly fewer toxic complications. Despite relatively poor results in some patient subgroups, CHOP remains the standard chemotherapy for this disease, against which all new regimens should be compared.

A Biologic Combination of Lenalidomide and Rituximab for Front-Line Therapy of Indolent B-Cell Non-Hodgkin's Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1714-1714 ◽  
Author(s):  
Nathan Fowler ◽  
Peter McLaughlin ◽  
Fredrick B. Hagemeister ◽  
Larry Kwak ◽  
Michelle Fanale ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Response Assessment ◽  
Response Rates ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Front Line ◽  
Line Therapy

Abstract Abstract 1714 Poster Board I-740 Background Despite advances in therapy and a better understanding of the natural history of indolent non-Hodgkins lymphomas (NHL), the optimal treatment for newly diagnosed patients (pts) has not been determined. While several chemotherapy regimens have response rates approaching 90%, toxicity is common with standard genotoxic combinations, particularly with retreatment at relapse. Lenalidomide is approved for the treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes with del(5q) mutation. In pts with indolent relapsed or refractory NHL, treatment with lenalidomide resulted in durations of response lasting > 16.5 months (Witzig et al JCO in press). Rituximab has been shown to have clinical activity in indolent NHL, both as a single agent and in combination with chemotherapy. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, stage III or IV, indolent NHL. Methods Previously untreated pts with indolent NHL and with measurable disease (>1.5 cm), were eligible for enrollment. For each 28-day cycle, pts received lenalidomide 20mg orally once daily on days 1-21 and rituximab 375mg/m2 intravenously on day 1, for up to 6 cycles of therapy. Response was assessed after 3 cycles and at the end of therapy using the International Working Group Response Criteria (Cheson et al 1999). Results At the time of this report, the planned accrual of 30 pts is complete. Response and adverse events are reported for the first 20 patients, which included 19 pts eligible for response assessment and 1 patient, who discontinued from study prior to response evaluation, secondary to leukocytoclastic vasculitis, which occurred during cycle 1. The median age was 55 yrs (range: 38-77) and 55% were male. The 20 currently evaluable patients include10 pts with follicular lymphoma, 8 pts with marginal zone lymphoma and 2 pts with small lymphocytic lymphoma. Of 19 pts eligible for response assessment, 18 completed 6 cycles of therapy and 1 pt, who was previously treated for Hodgkin's lymphoma, withdrew consent following cycle 3. The overall response rate was 84%, which included complete responses in 15 pts (79%; 58% CR/21% CRu) and 1 patient who achieved a partial response. An additional 3 pts (16%) remain with stable disease. By completion of 6 cycles of therapy, all 10 pts with follicular lymphoma achieved a complete response to therapy. No pt experienced progression of disease. The following grade 3/4 adverse events were reported; rash (6 pts), neutropenia (4 pts), myalgia (3 pts), neuropathy (1 pt), infection (1 pt), and fatigue (1 pt). Rashes, of all grades, occurred in 10 pts, which were mostly erythematous and transient, nonrecurring events. Response and toxicity assessment for the remaining 10 pts is ongoing and will be reported. Conclusion The biologic regimen of lenalidomide and rituximab as front line therapy produces excellent overall and complete response rates in pts with indolent B cell NHL. The combination was well tolerated with a manageable toxicity profile. Disclosures Fowler: Genentech: Honoraria, Speakers Bureau; BiogenIdec: Honoraria. Off Label Use: lenalidomide and rituximab for indolent B cell non-Hodgkin's lymphoma. McLaughlin:Genentech: Consultancy, Honoraria. Hagemeister:Genentech: Honoraria, Speakers Bureau; BiogenIdec: Honoraria, Speakers Bureau; Celgene: Consultancy. Kwak:Celgene: Research Funding. Samaniego:Celgene: Consultancy.

Phase II Study of Oral Fludarabine Phosphate in Relapsed Indolent B-Cell Non-Hodgkin's Lymphoma

2006 ◽  
Vol 24 (1) ◽  
pp. 174-180 ◽  
Author(s):  
Kensei Tobinai ◽  
Takashi Watanabe ◽  
Michinori Ogura ◽  
Yasuo Morishima ◽  
Yoshiaki Ogawa ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Response Rate ◽  
Phase Ii Study ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Fludarabine Phosphate ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Purpose Although intravenous (IV) fludarabine phosphate is effective against indolent B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study. Patients and Methods Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR). Results Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild. Conclusion Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation.

Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin's lymphoma.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 8036-8036 ◽  
Author(s):  
N. H. Fowler ◽  
P. McLaughlin ◽  
F. B. Hagemeister ◽  
L. W. Kwak ◽  
M. A. Fanale ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Response Rates ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

scholarly journals A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Walter Hanel ◽  
Beth A. Christian ◽  
Kami J. Maddocks ◽  
Narendranath Epperla ◽  
Basem M. William ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Response Rate ◽  
Immune Escape ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Median Number ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Introduction: Classical Hodgkin's Lymphoma (cHL) is characterized by an extensive inflammatory infiltrate with abundant Th2 and Treg cells which facilitate immune escape of Reed Sternberg (RS) cells and provides a growth promoting microenvironment by cytokine secretion and CD40/CD40L engagement. Our group previously show that ibrutinib irreversibly inhibits both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), a kinase important in Th2 signaling (Dubovsky et al Blood 2013). We hypothesized that the addition of ibrutinib to nivolumab would lead to deeper and more durable responses in cHL by normalizing the Th1/Th2 balance thus reversing immune escape of RS cells. We present results of a planned interim analysis of the first 10 patients enrolled with a data cutoff of June of 2020. Methods: This is a single arm, phase II, single institutional clinical trial testing the clinical activity of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who have received at least one prior line of therapy and who were either not candidates for or had a prior autologous stem cell transplant (ASCT). Prior treatment with nivolumab was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for 16 cycles. The primary objective was complete response rate (CRR) prior to cycle 7 assessed per Lugano criteria. Adverse events (AEs) were reported using CTCAE Version 4.0. Results: Of the first 11 cHL patients enrolled, one patient withdrew consent prior to initiating therapy. Of the remaining 10 patients, the median age was 41 years (range 20-84) and 4 patients (40%) were male. The median number of prior lines of treatment was 4.5 (range 1-11), 5 patients (50%) had prior ASCT, 8 patients (80%) had prior brentuximab, and 5 patients (50%) had prior nivolumab. Four of the five patients with prior nivolumab had progressed while receiving therapy while the remaining patient had stable disease upon completing nivolumab with a median time from the last nivolumab treatment of 15.6 months (range 0.7-23.2). Of the 10 patients who received treatment, one patient came off study after two cycles due to persistent grade 2 transaminitis lasting for several weeks attributed to nivolumab requiring high dose oral steroids. One patient came off study after cycle 9 due to grade 3 hematuria attributed to ibrutinib and another came off study due to a pericardial effusion after 8 cycles of ibrutinib maintenance. In the remaining patients, treatment was generally well tolerated with most AEs being grade 1-2 (Table 1). The median number of total cycles received was 9 (range 2-22). Of the 9 patients evaluable for response, 6 patients responded (ORR = 66%), 4 of whom had a complete response (CRR = 44%) with a median time to response of 2 months (Table 2, Fig.1). In intention-to-treat analysis, the ORR was 60% and CRR was 40% meeting our prespecified interim efficacy endpoint of a 30% CRR for trial continuation. Notably, of the 5 patients with prior nivolumab, 3 responded to nivolumab + ibrutinib (ORR = 60%), with one having a CR (CRR = 20%). Overall, at a median follow up of 9.5 months, both the median PFS and duration of response have not yet been reached, with 3 patients remaining in CR at the time of data cutoff. Three of 4 patients discontinued trial treatment to undergo SCT [2 allogeneic; 1 autologous]. Of the 2 allogeneic SCT patients, the first one underwent SCT 3 weeks after the last nivolumab infusion and developed multi-organ acute graft-versus-host disease (GVHD) followed by severe chronic GVHD requiring extracorporeal photopheresis. The second patient underwent allogeneic SCT 2 months following the last nivolumab infusion and had no acute GVHD and experienced only mild chronic GVHD which was medically managed. Conclusions: Although the numbers are small and further recruitment is ongoing (target n=17), the combination of ibrutinib and nivolumab was generally well tolerated and with high response rate with more than half of responding patients achieving a CR. In addition, responses were seen in patients with prior nivolumab treatment. Our results suggest a possible novel role for BTK inhibition in reversing nivolumab resistance in cHL, at least in some cases. Correlative studies including peripheral blood and tumor immune subset analyses are ongoing and the latest results will be presented at the meeting. Disclosures Christian: Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Maddocks:Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. William:Incyte: Research Funding; Dova: Research Funding; Celgene: Consultancy, Honoraria; Seattle Genetics: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Guidepoint Global: Consultancy. Jaglowski:Novartis: Consultancy, Research Funding; CRISPR: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy. Bond:Seattle Genetics: Honoraria. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Baiocchi:viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. OffLabel Disclosure: This trial uses ibrutnib in cHL to augment the responses of concurrent nivolumab administration.

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