A negative interim positron emission tomography/computerized tomography (PET/CT) after 1 to 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed, ...nonbulky stage I or II Hodgkin lymphoma (HL) predicts a low relapse rate. This phase 2 trial was designed to determine if a population of patients with early-stage disease can be treated with short-course ABVD without radiation therapy (RT) on the basis of a negative interim PET/CT, thereby limiting the risks of treatment. Between 15 May 2010 and 21 February 2013, 164 previously untreated patients with nonbulky stage I/II HL were enrolled, and 149 were included in the final analysis. Patients received 2 cycles of ABVD followed by PET. Deauville scores 1 to 3 were negative (≤ liver uptake) based on central review. PET− patients received 2 more cycles of ABVD, and PET+ patients received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus 3060-cGy involved-field RT. The primary objective was to determine 3-year progression-free survival (PFS) for the PET− group. One hundred thirty-five patients (91%) were interim PET−, and 14 patients (9%) were PET+. With median follow-up time of 3.8 years, the estimated 3-year PFS was 91% for the PET− group and 66% for the PET+ group (hazard ratio, 3.84; 95% confidence interval, 1.50-9.84; P = .011). There was 1 death as a result of suicide. Four cycles of ABVD resulted in durable remissions for a majority of patients with early-stage nonbulky HL and a negative interim PET. This trial was registered at www.clinicaltrials.gov as #NCT01132807.
•Interim PET− nonbulky stage I/II patients had 3-year PFS of 91% with 4 ABVD cycles and no RT.•Too few patients were interim PET+ to draw firm conclusions about efficacy of escalated BEACOPP plus involved-field RT.
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The ZUMA-7 (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) study showed that axicabtagene ciloleucel ...(axi-cel) improved event-free survival (EFS) compared with standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL); this led to its recent US Food and Drug Administration approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared with SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150 000 per QALY ($93 547 per QALY). axi-cel was no longer cost-effective if its 5-year EFS was ≤26.4% or if it cost more than $972 061 at a WTP of $150 000. Second-line axi-cel was the cost-effective strategy in 73% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive relapsed/refractory DLBCL is cost-effective compared with SOC at a WTP of $150 000 per QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine use of second-line chimeric antigen receptor T-cell therapy would add significantly to health care expenditures in the United States (more than $1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of chimeric antigen receptor T-cell therapy are needed to be affordable in many regions of the world.
Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In ...phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo–expanded autologous central memory–enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 106 in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8+ TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval CI: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4+ and CD8+ TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4+/CD8+ TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749.
•TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT.•Addition of a CD28 costimulatory domain to the CAR, plus changes to T-cell product manufacturing, resulted in improved T-cell expansion.
RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with ...hematologic malignancies was conducted.
Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity.
RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response.
RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.
Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel ...antifolate with promising activity.
Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received pralatrexate intravenously at 30 mg/m(2)/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS).
Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%).
To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.
Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable immunomodulatory effects and ...demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in preclinical models. We, therefore, developed a phase I study to evaluate the safety and preliminary efficacy of pembrolizumab with vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase II dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma NHL). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered twice daily on days 1-5 and 8-12 (dose-level DL1: 100 mg; DL2: 200 mg) and pembrolizumab (200 mg) was administered on day 1 of each 3-week cycle. Of six patients treated at DL1, one had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome SJS), and one of six had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, nine had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11% and 22% for FL and 45% and 55% for all DLBCL. Amongst DLBCL, the CR and ORR was 80% and 80% for PMBL and 17% and 33% for non-PMBL. In conclusion, pembrolizumab with vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL (clinicaltrials gov. Identifier: NCT03150329).
Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data ...are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.
•Pola-R-CHP is provisionally cost-effective compared with R-CHOP for the frontline treatment of DLBCL at a WTP of $150 000/QALY.•The cost-effectiveness of pola-R-CHP depends on its long-term outcomes ...(5-year PFS of at least 66.1% needed to remain cost-effective).
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In patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study (A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone R-CHP Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone R-CHOP in Participants With Diffuse Large B-Cell Lymphoma) reported a 6.5% improvement in the 2-year progression-free survival (PFS), with no difference in overall survival (OS) or safety using polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated the cost-effectiveness of pola-R-CHP for DLBCL. We modeled a hypothetical cohort of US adults (mean age, 65 years) with treatment-naive DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of pola-R-CHP and R-CHOP using a range of plausible long-term outcomes. Progression rates and OS were estimated from POLARIX. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year PFS of 69.6% with pola-R-CHP and 62.7% with R-CHOP, pola-R-CHP was cost-effective at a WTP of $150 000 (incremental cost-effectiveness ratio, $84 308/QALY). pola-R-CHP was no longer cost-effective if its 5-year PFS was 66.1% or lower. One-way sensitivity analysis revealed that pola-R-CHP is cost-effective up to a cost of $276 312 at a WTP of $150 000. pola-R-CHP was the cost-effective strategy in 56.6% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in PFS is maintained over time, pola-R-CHP is cost-effective compared with R-CHOP at a WTP of $150 000/QALY. However, its cost-effectiveness is highly dependent on its long-term outcomes and costs of chimeric antigen receptor T-cell therapy. Routine usage of pola-R-CHP would add significantly to health care expenditures. Price reductions or identification of subgroups that have maximal benefit would improve cost-effectiveness.
Kambhampati and colleagues examine the cost-effectiveness of the inclusion of polatuzumab vedotin (pola-R-CHP) in therapy for treatment-naïve diffuse large B-cell lymphoma. The POLARIX study showed a 6.5% improvement in 2-year progression-free survival (PFS) with no difference in overall survival using pola-R-CHP compared to R-CHOP. In their model, pola-R-CHP is cost-effective in 56.6% of iterations, suggesting marginal cost-effectiveness that is highly dependent on long-term PFS projections and the cost of CAR T-cell therapy.
We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma.
In this ...open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with ≤ 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability.
All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses CR and five partial responses PR). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue.
Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted.
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