PET -CT Adapted Therapy After 3 Cycles of ABVD for All Stages of Hodgkin Lymphoma. Preliminary Results in 193 Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1619-1619 ◽  
Author(s):  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Virginia Prates ◽  
Miguel A Pavlovsky ◽  
Lucia Zoppegno ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Cell Transplant ◽  
Bulky Disease ◽  
Radio Therapy ◽  
Anatomic Reduction ◽  
Pet Ct

Abstract Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PET-CT) is an important tool for treatment response assessment in Hodgkin Lymphoma (HL) treated with ABVD. It can predict response and overall outcome. The negative predictive value for PET-CT in patients (pts.) with HL is 90–94%. New recommendations define complete remission (CR) for HL as the lack of signs and symptoms of lymphoma with a negative PET-CT. OBJECTIVES: Reduce therapy in pts. who achieve early CR with negative PET-CT. Intensify treatment, only in pts. with positive PET-CT after 3 cycles of ABVD. Achieve CR, event free survival (EFS) and overall survival (OS), as good as in our historical control, when we used 3 or 6 cycles of ABVD plus involved field radio therapy (IFRT) in all pts.(LH-96) PATIENTS AND METHOD: Since October 2005, 200 newly diagnosed pts. with HL have been included in a prospective multicenter clinical trial (LH-05) All pts. received 3 cycles of ABVD and were then evaluated with a PET-CT (PET-CT +3) Pts. with a negative PET-CT+3 and absence of other signs or symptoms of lymphoma were considered in CR and received no further therapy. Pts with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions were considered in partial response (PR) and completed 6 cycles of ABVD and IFRT on PET-CT positive areas. Pts with less than PR received high doses of chemotherapy and an autologous stem cell transplant (ASCT). All pts were re-evaluated at the end of treatment with a new PET CT. One hundred and ninety three pts. have been evaluated. The median age at diagnosis was 29 years. One hundred and twenty five (65%) had localized stage (I-II) non bulky and 68 (35%) presented with advanced stage (III-IV), or bulky disease, 33 (17%) had bulky disease. RESULTS: One hundred and forty-eight (77%) achieved CR with negative PET-CT + 3. Forty-five (21%) were PET-CT+3 positive, 5 showed progressive disease. The other 40 pts. were in PR and completed a total of 6 ABVD + IFRT in PET-CT positive areas. Twenty eight achieved CR and 12 persisted with hypermetabolic lesions. Three died of progressive disease. After finishing planned treatment 178 pts. (92%) were in CR. With a median follow up of 39 months the EFS and OS at 36 months is 80% and 97% respectively. Patients with negative PET-CT +3 have an EFS of 86% compared to 61% for pts. with positive PET-CT+3 (P=0,001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET –CT+ 3. This last parameter together with age were the only ones with statistical significance (p=0.001 and 0.046 respectively). When comparing the results LH-05 with LH-96 there is no difference in EFS and OS at 36 months (83% vs. 85% and 97 vs. 96%) but in LH-05 only 23% received 6 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This reduces the exposure to chemo and radiotherapy. CONCLUSION: With PET-CT adapted therapy after 3 cycles of ABVD, 148 pts.(77%) received only 3 cycles of ABVD as initial therapy with an EFS and OS of 80% and 97% at 36 months. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS. In this interim analysis of PET-CT adapted therapy to all stages of HL, treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3. Continuing with ABVD after a positive PET-CT +3 can be considered insufficient. A longer follow-up and a larger number of pts. are necessary to confirm these results. Disclosures: No relevant conflicts of interest to declare.

PET-CT Adapted Therapy After 3 Cycles of ABVD for All Stages of Hodgkin Lymphoma. Interim Analysis in 173 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1772-1772
Author(s):  
Santiago Pavlovsky ◽  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Miguel Pavlovsky ◽  
Virginia Prates ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Cell Transplant ◽  
Advanced Stage ◽  
Event Free Survival ◽  
Bulky Disease ◽  
Free Survival ◽  
Pet Ct

Abstract Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an overall survival at 5 years of 80%. ABVD can be considered as gold standard for first line treatment for all stages of HL. Dividing patients (pts.) in different prognostic groups has aimed to reduce chemo and radio toxicity in those patients with good prognosis. A negative PET-CT, either early during treatment of ABVD or after completion of it, has shown to be a powerful prognostic tool (Hutchings: Blood 2006; Gallamini: Haematologica 2006). Our cooperative group has an experience with 584 patients with HL in early or advanced stage treated with 3 or 6 cycles of ABVD plus involved field radiotherapy with a complete remission (CR) of 91% and an event free survival (EFS) and overall survival (OS) at 60 months of 79% and 95%.(S Pavlovsky, Clin Lymp My & Leuk, 2010). Aims: Test the efficacy of treatment to all stages of HL adjusted to PET-CT results after 3 cycles of ABVD. Evaluate the outcome of pts. who have a negative PET-CT after 3 cycles of ABVD and receive no further treatment. Intensify therapy only in pts. who have persistent hyper metabolic lesions in PET-CT after 3 cycles of ABVD. Method: Since October 2005, 198 newly diagnosed pts. with HL have been included in a prospective multicenter trial. Initially all patients received 3 cycles of ABVD. After the third cycle, pts. were evaluated with a PET-CT. Those pts. who achieved CR with a negative PET-CT, received no further treatment. Those with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions by PET-TC after 3 ABVD were considered in partial remission (PR) and completed 6 cycles of ABVD and radiotherapy (RT) on PET-CT positive areas. Those patients with less than PR after 3 cycles of ABVD received ESHAP and if CR, high doses of chemotherapy and an autologous stem cell transplant (ASCT). All patients were re-evaluated at the end of treatment. The median follow up is of 30 months (3-62). Results: One hundred and seventy three patients completed three cycles of ABVD followed by a PET-CT. The median age at diagnosis was 29 years. One hundred and thirty-six (79%) had localized stage (I-II) at diagnosis and 37 (21%) presented with advanced stage (III-IV). Of 155 pts. 77 (50%) pts had IPS 0–1, 66 (43%) had IPS 2–3 and 12 (8%) had IPS 4–5. Twenty six (17%) pts. had bulky disease at diagnosis. One hundred and thirty-seven (79%) pts. achieved CR with negative PET-CT after 3 cycles of ABVD. Thirty-six (21%) were PET-CT positive, of them 32 pts achieved PR and completed a total of 6 cycles of ABVD plus RT in hyper metabolic lesions. Twenty five achieved CR (72%), 5 persisted with PR and 2 died of progressive disease. Four pts showed progressive disease (PD) after 3 ABVD and received ESHAP and ASCT, 2 achieved and remained in CR, 1 is in PR and 1 died of progressive disease. Of 173 pts who completed treatment with ABVD × 3 cycles, ABVD × 6 cycles plus RT on PET-TC positive areas or ESHAP plus ASCT, 164 pts (95%) achieved CR. Of these 164 pts., 14 pts (8%) relapsed. The EFS and OS at 36 months is 83% and 97% respectively. Patients with early negative PET-TC have an event-free survival of 87% compared to 62% (P=0,001) for pts with early positive PET CT. The OS at 36 months was 100% versus 86% respectively (<0.001). Conclusion: Treating patients with ABVD, evaluating response after 3 cycles with PET-CT, and adapting further therapy, leads to a high rate of CR avoiding more aggressive chemotherapy and radiotherapy. Three courses of ABVD without RT are adequate in patients with early CR defined by negative PET-CT. In early positive PET-CT it is possible to intensify therapy improving the otherwise bad prognosis; more aggressive treatment might also be suitable. These results need to be confirmed by a larger group of patients and a longer follow-up. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tumor Associated Antigen Specific T Cells Given in Combination with Nivolumab for the Treatment of Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18 ◽  
Author(s):  
Hema Dave ◽  
Mimi Mai ◽  
Madeline Terpilowski ◽  
Keri Toner ◽  
Maja Stanojevic ◽  
...  
Keyword(s):  
T Cells ◽  
Complete Remission ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Stable Disease ◽  
Peripheral Blood ◽  
Progressive Disease ◽  
Cell Transplant ◽  
Hematopoietic Stem

Background: Hodgkin Lymphoma (HL) Reed Sternberg cells express tumor associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA specific T cells (TAA-T) targeting WT1, PRAME and Survivin were safe and associated with prolonged time to progression in solid tumors (Hont JCO 2019). Hence, we evaluated whether TAA-T cells are safe and elicit anti-tumor effects in patients with relapsed/refractory (rel/ref) HL. We further evaluated the safety of Nivolumab following the TAA-T infusion and its effect on the persistence of the TAA-T cells in vivo. Methods: TAA-T products were generated from patients or healthy donors on 2 trials (NCT02203903; NCT03843294). Thirteen patients underwent procurement for product generation and 10 patients (2 allogeneic; 8 autologous) were infused TAA-T for rel/ref HL or as consolidation after autologous hematopoietic stem cell transplant (HSCT) at cumulative doses ranging from 0.5 X107 to 4 X107cells/m2. Patients were monitored for six weeks for safety and for response until disease progression. Seven patients received Nivolumab starting at 8 weeks after the first TAA-T infusion until disease progression or unacceptable toxicity. Results: TAA-T products (n=10) were polyclonal CD3+ T cells (Median 97%; 80.9-99.5%), comprised predominantly of CD4+ helper T cells (Median 10.5%; 1.74-20%) and CD8+ cytotoxic T cells (Median 70%; 29.3-87.5%). Specificity of TAA-T products was tested using Interferon-ϒ(INFϒ)-enzyme-linked immunospot (ELIspot) assay and defined as ≥ 2x spot-forming cells (SFC)/2.5X105cells against the tumor antigen as compared to irrelevant control antigen Actin(Figure 1). The median TAA specificity of the products was 2 antigens (range 0-3). All products were polyfunctional secreting INF-ϒ and TNF-α upon restimulation with tumor antigens (Fig 1). Median age of patients was 36yrs (range16-53). Patients had received a median 6 lines of therapy including HSCT prior to receiving TAA-T. Median follow-up post TAA-T#1 was 6 months (range 32 days-2.5yrs). There were no dose limiting toxicities observed within the 6 week safety monitoring period. In patients receiving Nivolumab post TAA-T, there were no increased immune related events over expected. One patient had Grade 3 seizures, possibly related to Nivolumab, 2 patients developed hypothyroidism requiring thyroid supplements and one patient developed myositis and discontinued Nivolumab after 5 months. The 2 patients who received TAA-T (1 donor derived and one autologous) as consolidation post HSCT achieved a continued complete remission (CCR) for 2+ years. Of the 8 patients with rel/ref HL at the time of infusion, 1 had disease progression at 6 weeks. He then received Nivolumab off protocol and achieved complete remission (CR) but developed Grade 4 GVHD. The remaining 7 patients had stable disease (SD) at 6 weeks. At a median follow-up of 6 months (32 days-2.5 years), 1 patient had progressive disease(PD) at 3 months, 1 patient had a complete metabolic response at 6 months and proceeded to allogeneic HSCT for definitive cure. 2 patients had PD at 6 months and the other 2 patients continue with SD at 6 months and remain on Nivolumab (Fig 1). All patients with objective responses (stable disease or better) recovered functional TAA-T cells in the peripheral blood at 3 months as detected by anti-Interferon-ϒ ELISPOT and reported as mean SFC/1 X105 cells for WT1(14±SD18.1); PRAME (17.4±15.3) and Survivin (4.5±7) compared to those with progressive disease with mean SFC/1 X105 cells for WT1 1.4(±2.3); PRAME (6.7±15.5) and Survivin (0.8±1.2). To evaluate TAA-T persistence, unique T cell receptor clonotypes defined in the TAA-T product and not present at baseline were detected in the peripheral blood 6 weeks post TAA-T, long-term persistence data and evaluating the effect on the TCR repertoire when adding nivolumab are pending. Conclusion: TAA-T cells given in combination with Nivolumab were safe when administered to patients with rel/ref HL with prolonged clinical responses (ranging from SD to CCR) observed in multiply relapsed patients. Disclosures Glenn: Genentech: Research Funding. Hanley:Mana Therapeutics: Honoraria, Other: Board Member; Cellevolve: Honoraria, Other: Board(Scientific Advisory Board). Bollard:Mana Therapeutics: Other: IP.

Outcome of Patients with Advanced Hodgkin Lymphoma Who Are Either Refractory to or Relapsed After Primary Therapy with the Stanford V Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4828-4828
Author(s):  
Lauren S. Maeda ◽  
Richard T. Hoppe ◽  
Saul A. Rosenberg ◽  
Sandra J. Horning ◽  
Ranjana H. Advani
Keyword(s):  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Prognostic Score ◽  
Initial Diagnosis ◽  
Cell Transplant ◽  
Primary Therapy ◽  
Advanced Stage ◽  
Bulky Disease ◽  
Hematopoietic Stem

Abstract Abstract 4828 Purpose: Stanford V is an abbreviated combined modality approach for the treatment of advanced stage Hodgkin lymphoma (HL). This regimen was developed with the aim of shortening the duration of chemotherapy, limiting the radiotherapy (RT) to a modified involved field and thereby potentially reducing short and long term toxicity while maintaining or improving cure rates. Specifically the chemotherapy regimen has significantly lower cumulative doses of adriamycin, bleomycin and alkylating agents compared to other standard regimens such as ABVD or escalated BEACOPP. We have previously reported excellent outcomes with this regimen with a freedom from progression (FFP) of 89% and overall survival (OS) of 96% (Horning, S.J., et al., J Clin Oncol 2002, 20:630-7). The purpose of this study was to determine the outcome of patients (pts) treated with secondary therapy after failing Stanford V. Methods: Pts with advanced stage HL who had either refractory disease or had relapsed after primary therapy with Stanford V, were retrospectively identified from the HL database. We analyzed this group of patients for risk factors, salvage therapy, and treatment outcome. Results: Between May 1989 and March 2003, 167 pts were treated on protocol. At a median follow-up of 12.8 years the outcomes are excellent with a 10-year FFP and OS of 87% and 93%, respectively. Therapy failed in 19 pts (11%) of which 16 relapsed and 3 did not complete the intended treatment (disease progression n=2, and muscle pain and hyponatremia n=1). The median age of pts who failed therapy was 31 years (range 21 – 58) with a median time to progression of 5.1 months (range 0.2 – 41.4). 11 pts relapsed at 0 to 12 months from completion of therapy and 8 pts relapsed at > 12 months. At initial diagnosis 5 had stage I/II disease with bulky mediastinum, 5 stage III and 9 stage IV disease. The International Prognostic Score (IPS) at initial diagnosis was 0–1 (n=4), 2–3 (n=10) and 4–7 (n=5). 13/19 (68%) pts relapsed outside the RT field, 2 infield, 3 both infield and outside and 1 unknown. 7/19 pts in whom therapy failed had bulky disease and of these 5 failed outside the RT field. Relapse was detected clinically in 12 pts, and on surveillance positron emission tomography scan performed every 3 to 6 months in 5 pts who were asymptomatic (2 pts unknown). 14/19 (74%) pts received secondary therapy with a platinum-containing regimen (ICE or DHAP) with an overall response rate (ORR) of 91% (complete response [CR] n=1, partial response [PR] n=9, progressive disease [PD] n=1, unknown response n=3), followed by an autologous hematopoietic stem cell transplant. 5 pts were treated with non-transplant regimens consisting of chemotherapy with MOPP/ABV + RT (n=2), ChlVPP (n=1), oral cyclophosphamide (n=1) and procarbazine/alkeran/adriamycin/etoposide (n=1), with an ORR of 80% (CR n=4). Reasons for non-transplant therapy were neuropathy (n=1), pt preference (n=1), liver disease (n=1), and unknown (n=2). 11 of the 19 pts in whom Stanford V failed died (disease progression n=3, second malignancy n=2, graft failure n=1, infection n=1, liver failure n=1, cardiac arrest n=1, suicide n=1 and unknown n=1). At a median follow-up of 8 years, the disease-specific survival (DSS), FFP and OS for pts with refractory or relapsed disease after Stanford V was 84%, 63% and 42%, respectively. Outcome of pts who relapsed within a year was worse than pts who relapsed > 1 year with an OS of 36% versus 50%, respectively. There was no difference in FFP for these groups, 64% versus 63%, respectively. Conclusions: The outcome of pts with advanced HL is excellent with the Stanford V regimen. For the 11% of pts in whom front line therapy fails, secondary therapy is effective with a DSS of > 80%. The majority of pts (84%) failed at distant sites suggesting that more aggressive upfront chemotherapy may have been beneficial in these pts. Future efforts will aim at identifying this subset upfront. Pts who relapse within a year have a worse outcome despite salvage and for this subgroup, newer therapies are warranted. Disclosures: Horning: Genentech: Employment.

scholarly journals Brentuximab Vedotin with Chemotherapy in Frontline Treatment of Classic Hodgkin Lymphoma Nodular Sclerosis Syncytial Variant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-29
Author(s):  
Raphael Eric Steiner ◽  
Melody R. Becnel ◽  
Branko Cuglievan ◽  
Ranjit Nair ◽  
Prachee Singh ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Brentuximab Vedotin ◽  
Phase Iii ◽  
Cytotoxic Therapy ◽  
Bulky Disease ◽  
Nodular Sclerosis ◽  
Classic Hodgkin Lymphoma ◽  
Pet Ct ◽  
Frontline Treatment

BACKGROUND: Classic Hodgkin lymphoma (cHL) Nodular Sclerosis (NS) is the most common subtype of cHL and has a good prognosis. However, an uncommon variant of cHL NS, the syncytial variant (cHL NS-SV), represents an entity with a worse clinical outcome with conventional frontline cytotoxic therapy. Nevertheless, in the pivotal phase III study ECHELON-1, Brentuximab Vedotin (BV), doxorubicin, vinblastine, and dacarbazine (BV+AVD) while demonstrating a superior efficacy, unfortunately more febrile neutropenia (FN) and peripheral neuropathy (PN) were observed compared to bleomycin+AVD (ABVD) as frontline treatment of advanced-stage classical Hodgkin's lymphoma (cHL) (Straus et al Blood 2020). It is unknown whether BV combined with chemotherapy would improve the inferior prognosis of cHL NS-SV. METHODS: After obtaining institutional research approval, we retrospectively reviewed the characteristics and outcomes of adult cHL NS-SV patients, treated per physician preference with frontline BV combined with cytotoxic therapy, either as standard of care (SOC) or in a clinical trial (NCT01712490, NCT03646123 and NCT01060904) between 7/2010 and 7/2020. cHL NS-SV diagnosis was based on morphology and Immunophenotype. Bulky disease was defined as mass&gt;10cm or mediastinal mass &gt;1/3 of thoracic diameter at T5-T6. Lymph node regions were defined by the German Hodgkin Study Group (GHSG). Treatment consisted of 0.9 or 1.2 mg/kg of BV and standard dose ABVD or AVD or D, intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. All patients received support with pegfilgrastim. Response assessment was based on positron emission tomography/computerized tomography (PET/CT). Follow-up time was calculated from the date of pre-treatment baseline lab measurement to relapse date or death date, whichever happened first. Patients with no event were censored at the last follow-up date. RESULTS: Among the 11 patients included in the analysis, the median age was 29 (range 19-59 years), 27.2% were female, and 90.9% were Caucasian. All patients had Eastern Cooperative Oncology Group (ECOG) 0-1, 72.7% of patients had B-symptoms and 81.9% had stage III or IV disease. The median size of the largest lesion was 9.0 cm, 45.5% of patients had bulky disease, 63.6% had extranodal disease, 72.7% had &gt;3 GHSG involved nodal sites and median International Prognostic Score was 4. Overall, all patients received 6 cycles of therapy, 63.6% received BV+AVD, 27.3% received BV+ABVD and 1 patient received SOC BV with dacarbazine because of previous anthracycline exposure. The interim PET/CT showed response in all patients with Deauville score (DS) of 2-3 in 45.5% and 4 in 54.4%. The end-of-therapy PET/CT showed DS of 1-3 in 90.1% and 4 in 8.9%. The latter patient had the most voluminous bulk of this study. To date, no patient received additional systemic therapy or consolidative radiotherapy after completion induction therapy. With a median follow-up time of 14 months (range 5-82 months), no patient had relapse and all were still alive (Progression-Free Survival and Overall Survival of 100%). CONCLUSIONS: BV combined with cytotoxic therapy such as BV+AVD is a highly effective treatment strategy for patients with cHL NS-SV. Further studies are required to evaluate whether frontline therapy of BV+AVD could improve the outcome of the higher-risk subgroup cHL NS-SV. Table Disclosures Lee: Oncternal Therapeutics:Research Funding;Guidepoint Blogal:Consultancy;Aptitude Health:Speakers Bureau;Takeda:Research Funding;Seattle Genetics:Research Funding;Celgene:Research Funding;Bristol-Myers Squibb:Consultancy, Research Funding.

Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): Primary analysis of the phase 2 Elara trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7508-7508
Author(s):  
Stephen J. Schuster ◽  
Michael J. Dickinson ◽  
Martin H. Dreyling ◽  
Joaquín Martínez ◽  
Arne Kolstad ◽  
...  
Keyword(s):  
High Risk ◽  
Progressive Disease ◽  
Response Rate ◽  
B Cell Lymphoma ◽  
Disease Assessment ◽  
Cell Transplant ◽  
Phase 2 ◽  
Primary Analysis ◽  
Bulky Disease

7508 Background: Most pts with r/r FL experience multiple relapses and progressively worse clinical outcomes with each line of therapy, underlining a need for novel therapies. Tisa-cel has demonstrated durable responses and manageable safety in adult pts with r/r diffuse large B-cell lymphoma. Here we report the primary analysis of ELARA, an international, single-arm phase 2 trial of tisa-cel in adult pts with r/r FL. Methods: Eligible pts (≥18 y) had r/r FL (grades [Gr] 1-3A) after ≥2 lines of therapy or had failed autologous stem cell transplant. Bridging therapy was permitted followed by disease assessment prior to tisa-cel infusion. Pts received tisa-cel (0.6-6×108 CAR+ viable T cells) after lymphodepleting chemotherapy. The primary endpoint was complete response rate (CRR) by central review per Lugano 2014 criteria. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Predefined primary analysis occurred when ≥90 treated pts had ≥6 mo of follow-up. Results: As of September 28, 2020, 98 pts were enrolled and 97 received tisa-cel (median follow-up, 10.6 mo). At study entry, median age among treated pts was 57 y (range, 29-73), 85% had stage III-IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. The median number of prior therapies was 4 (range, 2-13); 78% of pts were refractory to their last treatment (76% to any ≥2 prior regimens) and 60% progressed within 2 y of initial anti-CD20–containing treatment. Of 94 pts evaluable for efficacy, the CRR was 66% (95% CI, 56-75) and the ORR was 86% (95% CI, 78-92). CRRs/ORRs were comparable among key high-risk subgroups. Estimated DOR (CR) and PFS rates at 6 mo were 94% (95% CI, 82-98) and 76% (95% CI, 65-84), respectively. Of 97 pts evaluable for safety, 65% experienced Gr ≥3 adverse events within 8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (per Lee scale) occurred in 49% of pts (Gr ≥3, 0%). Any-grade neurological events (per CTCAE v4.03) occurred in 9% of pts (Gr 3, 0%; Gr 4, 1 pt and recovered). Three pts died from progressive disease. Cellular kinetic parameters for tisa-cel were estimated using transgene levels (by qPCR) in peripheral blood. Cmax and AUC0-28d were similar between responders (CR or partial response) and non-responders (stable or progressive disease). Maximum transgene levels were reached by a median of 10 days in responders and 12.9 days in non-responders; transgene persistence was detected up to 370 days and 187 days, respectively. Conclusions: These data demonstrate the efficacy and acceptable safety of tisa-cel in pts with r/r FL, including high-risk pts after multiple lines of prior therapy, and suggest that tisa-cel may be a promising therapy for pts with r/r FL. Clinical trial information: NCT03568461.

scholarly journals Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2836-2836
Author(s):  
Judah Friedman ◽  
Hun Ju Lee ◽  
Linda Ho ◽  
Ian W. Flinn
Keyword(s):  
Peripheral Neuropathy ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Performance Status ◽  
Laboratory Data ◽  
Brentuximab Vedotin ◽  
Stage Iii ◽  
Cell Transplant ◽  
Bulky Disease

Background For patients with advanced classical Hodgkin lymphoma (cHL), the most common frontline regimen has historically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which originated in 1975 (Connors 2018). However, up to 30% of patients treated with ABVD as frontline therapy will relapse or are refractory to treatment (Canellos 1992; Carde 2016; Gordon 2013). Additionally, bleomycin is associated with potentially fatal pulmonary toxicity (Canellos 2004; Martin 2004), and vinblastine is associated with neutropenia and peripheral neuropathy. Brentuximab vedotin (BV, ADCETRIS®) has been approved for the treatment of adult patients with previously untreated Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine based on the results of the ECHELON-1 study (Connors 2017). Data reported from ECHELON-1 showed patients randomized to the BV + doxorubicin, vinblastine, and dacarbazine (A + AVD) treatment arm had a statistically significant 23% risk reduction in modified PFS events vs patients randomized to the ABVD arm of the study. The combination of BV plus nivolumab was reported as showing potential for the treatment of cHL. The combination was evaluated as a potential frontline treatment option for patients with cHL who are over 60 years of age and ineligible for or declining conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 patients and the regimen appears well tolerated in this population. In another trial in 62 patients in the first salvage setting, the combination produced a 61% CR rate (Herrera 2018) and the patients were able to undergo subsequent stem cell transplant. BV and nivolumab have been combined separately with doxorubicin, vinblastine, and dacarbazine and shown to be active and well tolerated. Furthermore, BV has been evaluated in combination with just doxorubicin and dacarbazine, omitting vinblastine, in 34 patients with previously untreated non-bulky stage I/II cHL and showed 100% complete response rate at end of treatment (EOT) and PFS and OS rates of 100% at last follow up (median=15 months; Abramson 2018). This combination resulted in a low incidence of neutropenia and alopecia, and moderate (Grade 1 or 2) peripheral neuropathy. It is therefore reasonable to expect that the combination of BV, nivolumab, doxorubicin, and dacarbazine (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Study Design SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate growth factor prophylaxis plus BV in combination with AVD in patients with stage III and IV cHL (Part A). A second cohort has been added to the study (Part B), which will evaluate the combination of AN + AD in this patient population. The primary objective of Part B is to estimate the CR rate at EOT with AN + AD in patients with previously untreated advanced cHL. All enrolled patients will be 12 years or older, with an ECOG performance status of ≤2. Patients in Part B will be treatment-naïve with Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky disease. Patients must have bidimensional measurable disease, as documented by radiographic technique, and qualifying baseline laboratory data. Patients will be excluded if they have nodular lymphocyte predominant HL or have symptomatic neurologic disease that compromises normal activities of daily living or requires medication. Patients with known cerebral or meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy, will also be excluded. Approximately 50 patients will be enrolled in Part B. All patients will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. All study drugs will each be administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles of treatment. Efficacy will be assessed by PET and CT scans at Cycle 2 and EOT. Disease assessments will be performed during follow-up every 3 months for the first year, every 6 months for 2 additional years, and then per institutional standard of care. Disease response and progression will be assessed by investigators using the Lymphoma Response to Immunomodulatory Therapy Criteria modification of Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2016). Disclosures Friedman: Amgen: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding.

Continuous Infusion Cyclophosphamide as Salvage Therapy for Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4942-4942
Author(s):  
Binu Malhotra ◽  
David L Porter ◽  
Edward A. Stadtmauer ◽  
Stephen J. Schuster ◽  
Dan T. Vogl
Keyword(s):  
Multiple Myeloma ◽  
Continuous Infusion ◽  
Median Duration ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Free Survival ◽  
Refractory Multiple Myeloma

Abstract Abstract 4942 Background Patients with relapsed or refractory multiple myeloma (MM) are resistant to most therapies. In this study, we assess the efficacy and tolerability of continuous infusion (CI) cyclophosphamide in a group of heavily pre-treated patients with relapsed/refractory MM. Methods Charts of all patients treated with CI cyclophosphamide for relapsed/refractory MM between 01/2003 and 12/2008, at the Hospital of University of Pennsylvania, were identified and reviewed. Patients who had received at least one cycle of CI cyclophosphamide were included for the analysis. The dose of cyclophosphamide ranged between 200-300 mg/m2/day CI for 4 days. Duration of each cycle was planned at 28 days. Response was assessed using the international uniform response criteria for MM. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria, version 4. Results We treated 24 patients with CI cyclophosphamide. The median age was 60.5 years (range 33-75 years) and 66% were male. Patients had received a median of 5 prior regimens (range 2.0 to 11.0) and the median duration of time from diagnosis to treatment with CI cyclophosphamide was 5 yrs (range 0.38-22 yrs). Cyclophosphamide was started in 19 patients for management of progressive disease, and in 5 patients for lack of response or adverse effects from prior therapies. Prior therapies included: bortezomib (in all patients), lenalidomide (in 96% of patients) and autologous stem cell transplant (ASCT - once in 46%, and twice in 29%) among others. The median number of cyclophosphamide cycles administered until the time of last follow up was 4.0 (range 1.0-43.0). Treatment was ongoing in 4 patients at the time of last follow up, and two patients with stable disease were being observed without therapy. Median overall survival for all patients was 22.3 months (95% CI 10.04-34.53) and median progression free survival (PFS) was 7.4 months (95%CI 4.12-10.69). Partial response was noted in 4 patients, who had a median duration of response of 4.2 months and median time to best response of 0.8 month. Disease was stabilized in 14 additional patients. Disease progressed despite therapy in 6 patients, and in 4 of those progressive disease was evident from cycle one. Cytopenias were noted in 8 patients, with 4 related to the treatment with cyclophosphamide, but in only one case did this lead to discontinuation of therapy. Conclusion In our experience with 24 patients, monthly cycles of continuous infusion cyclophosphamide was a safe and effective method of treating relapsed or refractory multiple myeloma resulting in a prolonged progression free survival in very heavily pretreated patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Myocardial Metabolic Response Predicts Chemotherapy Curative Potential on Hodgkin Lymphoma: A Proof-of-Concept Study

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 971
Author(s):  
Cecilia Marini ◽  
Matteo Bauckneht ◽  
Anna Borra ◽  
Rita Lai ◽  
Maria Isabella Donegani ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cox Regression ◽  
Metabolic Response ◽  
Progression Free Survival ◽  
Disease Relapse ◽  
Cox Regression Analysis ◽  
Normal Tissues ◽  
Pet Ct ◽  
Genome Sharing

Genome sharing between cancer and normal tissues might imply a similar susceptibility to chemotherapy toxicity. The present study aimed to investigate whether curative potential of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predicted by the metabolic response of normal tissues in patients with Hodgkin lymphoma (HL). METHODS: According to current guidelines, 86 patients with advanced-stage (IIB-IVB) HL, prospectively enrolled in the HD0607 trial (NCT00795613), underwent 18 F-fluorodeoyglucose PET/CT imaging at diagnosis and, at interim, after two ABVD courses, to decide regimen maintenance or its escalation. In both scans, myocardial FDG uptake was binarized according to its median value. Death and disease relapse were recorded to estimate progression-free survival (PFS) during a follow-up with median duration of 43.8 months (range 6.97–60). RESULTS: Four patients (4.6%) died, while six experienced disease relapse (7%). Complete switch-off of cancer lesions and cardiac lighting predicted a favorable outcome at Kaplan–Mayer analyses. The independent nature and additive predictive value of their risk prediction were confirmed by the multivariate Cox regression analysis. CONCLUSION: Susceptibility of HL lesions to chemotherapy is at least partially determined by factors featuring the host who developed it.

scholarly journals The Platelet Millionaire: A Rare Cause of Thrombocytosis in an Adolescent

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5391-5391
Author(s):  
Ritika Walia ◽  
Theresa Sepulveda ◽  
Sharon Wretzel ◽  
Philip H Brandt
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Primary Care Physicians ◽  
Conflicts Of Interest ◽  
Abdominal Ultrasound ◽  
Cell Transplant ◽  
Peripheral Smear ◽  
Hematopoietic Stem ◽  
Marrow Fibrosis

Objectives: Primary myelofibrosis is rare in pediatrics, often manifesting as persistent idiopathic thrombocytosis.Transitions from pediatric to adult medical care can be complicated by workup requiring invasive procedures. J.M., an 18-year-old healthy male, presented for excessive gingival bleeding after wisdom tooth extraction. Workup revealed persistent thrombocytosis to 1,165K, prompting a referral to hematology-oncology. A peripheral smear was notable for many platelets but normal RBC morphology. He had splenomegaly on abdominal ultrasound and a decreased von-Willebrand's activity to antigen ratio, suggesting acquired vWD. A bone marrow biopsy was advised; however, J.M. became lost to follow up for over 9 months owing to self-reported anxiety about the procedure. He remained asymptomatic in this interim until he re-presented to clinic for easy bruising, with no other evidence of bleeding at the time. The biopsy was pursued, revealing hypercellular marrow for age with left shifted granulocytic and erythroid maturation, abnormal megakaryocytes, and 3% blasts. This was consistent with primary early myelofibrosis (PMF), positive for MF-1, CALR, and TP53 mutations and negative for JAK2 and BCR-ABL. He was transitioned to adult hematology, maintained on baby aspirin, and referred for potential allogeneic hematopoietic stem cell transplant (HSCT). PMF is characterized by marrow fibrosis due to secretion of fibroblast growth factor by clonally proliferative megakaryocytes. It is a disease of adulthood, with 67 years being the median age at diagnosis. Only 100 cases have been reported in children, most of which are secondary to AML, ALL or other malignancies.1 Most patients present with complications of extramedullary hematopoiesis or bleeding.2 Diagnosis is suggested by a leukoerythroblastic picture on peripheral smear and confirmed with a bone marrow biopsy "dry tap" revealing marrow fibrosis.3 Prognosis in pediatric PMF is difficult to predict but outcomes tend to be worse;4 TP53 mutation is rare and based on limited adult studies may portend a poorer prognosis.5 Our young patient with this rare mutation was therefore referred for HSCT evaluation. Further complicating this case was J.M.'s anxiety, which delayed definitive diagnosis by biopsy. He only agreed to it when, at the med-peds clinic, the concept of local pain management was discussed. Anticipation of upcoming procedures by primary care physicians and close follow-up is especially important for patients transitioning from pediatric to adult providers. Disclosures No relevant conflicts of interest to declare.

Checkpoint Inhibition before Axicabtagene Ciloleucel Cell Therapy in Primary Mediastinal B-Cell Lymphoma (PMBCL) Treated in Real Life Setting

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Annalisa Chiappella ◽  
Anna Dodero ◽  
Anna Guidetti ◽  
Filippo Bagnoli ◽  
Vanessa Aragona ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Bridging Therapy ◽  
Bulky Disease ◽  
Car T

Background: Eighty-five percent of PMBCL are cured by standard therapy, but the outcome of refractory/relapsed (R/R) PMBCL is very poor. Checkpoint inhibitors (CPIs) have shown promising activity in relapsed PMBCL. Axibactagene ciloleucel (axi-cel) CAR-T cell therapy, can induce durable responses and is currently approved for the treatment of adult patients with R/R PMBCL. Aims of this analysis were: to register all Italian PMBCL patients candidate to CAR-T in the 6 active centers;to evaluate the intention to treat overall response rate (ORR, complete [CR] and partial response [PR]) in patients treated with axi-cel and CPIs for salvage or bridging before CAR-T and for relapse after CAR-T;to evaluate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Methods: In August 2019 the Italian Drug Agency (AIFA) approved axi-cel; before the reimbursement by AIFA, an expanded access program supported by Kite/Gilead started. One patient slot per month per qualified center was available. Patients were included in a large national CAR-T prospective observational study approved by ethics committees. Results: Since April 2019 to March 2020, 20 R/R PMBCL were evaluated and 18 were apheresized in order to receive axi-cel; 2 were excluded because active CNS disease in one, and eligibility to transplant, while in CR, in the second one. Their clinical characteristics were: median age 38 years (range 22-50), male 8 (44%), stage II 6 (33%), advanced stage III/IV 12 (66%), bulky disease 6 (33%); LDH upper than normal 3 (2%). Median number of prior lines was 3 (2-6); 5 patients (28%) had a previous autologous stem cell transplant and 12 (66%) received a prior radiotherapy. The majority of patients, 16 (89%) were refractory to the last treatment when they were evaluated for CAR-T eligibility; 9 of 18 patients had CPI exposure before leukoapheresis: 6 pembrolizumab and 3 nivolumab in combination with brentuximab-vedotin. No manufacturing failures were reported. Bridging therapy was performed in 16 of 18 patients (88%). Seventeen patients (94%) received lymphodepleting Flu-Cy chemotherapy and only 16 pts received CAR-T for central nervous system (CNS) progression during bridging therapy (n=1) and respiratory failure due to pneumonia (n=1); the 2 patient not infused were exposed to CPIs. Median vein to vein time was 40 days (30-79). Median follow-up time for infused patients was 209 days (9-444). CRS was observed in 12 of 16 infused patients: 5 grade 2 and 7 grade 1. ICANS (2 grade 1, 2 grade 2, 1 grade 3) was recorded in 5 patients. No differences regarding CRS and ICANS occurrence were observed in patients exposed or not to CPIs. At 30-days after the infusion, all the 16 infused patients were evaluable for response: 7 (44%) CR, 5 (31%) PR, with ORR 75%, 3 (19%) stable disease (SD) and 1 (6%) progressive disease (PD). Two patients in PR at 30 days converted to CR at 90 days, with continuous CR at 180 days; all the 3 patients in SD and 1 out of 5 in PR at 30 days progressed at 90 days. Considering the 9 patients exposed to CPIs before CAR-T, 7 out of 9 were infused and all the 7 infused were evaluable for response: 2 (29%) CR, 4 (57%) PR, with ORR 86%, and 1 (14%) died because of a rapid CNS progression after infusion. Two patients in PR at 30-days converted to CR at 90-days, one with continuous CR at 180 days after CAR-T. Conclusions: In our series of 16 infused patients, axi-cel was effective with an ORR of 75% (CR 44%) at 30-days after CAR-T infusion and ORR of 54% (CR 46%) in the 13 patients evaluable at the median follow-up time (180-days after CAR-T infusion). It is important to note the 4 patients from the original real life cohort never received axi-cel. It is noteworthy that ORR was 86% in patients receiving CPIs before CAR-T and 75% in those not exposed to CPIs. With the limitation of small number, the exposure of immune-checkpoint inhibitors seems not to affect negatively response rate and adverse events. Disclosures Chiappella: Janssen: Honoraria; Iqone: Honoraria; Servier: Honoraria; Roche: Honoraria; Celgene: Honoraria; Gilead-Kite: Honoraria; Takeda: Honoraria. Zinzani:Bayer: Consultancy. Corradini:BMS: Other; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria.

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