Hodgkin’s lymphoma

Anti-PD-1 Drugs Impress as Frontline Therapy for Early, Unfavorable Hodgkin’s

Posted by

0


3-year PFS of 99%, OS of 100% with nivolumab-chemo, high response rate with pembrolizumab

Patients with early unfavorable-risk Hodgkin lymphoma had near-perfect 3-year survival outcomes following concurrent or sequential treatment with nivolumab (Opdivo) and chemotherapy, a prospective phase II study showed.

After a median follow-up of 40 months, the 3-year progression-free survival (PFS) rate was 99% and the 3-year overall survival (OS) rate was 100%. No secondary malignancies had been reported, and no new safety signals had emerged. Global quality of life improved or did not deteriorate during follow-up, reported Paul J. Bröckelmann, MD, of the University of Cologne in Germany.

“The efficacy is outstanding in this setting, and especially patients who are given a PR [partial response] do not seem to have disease activity and convert to a CR [complete response] during follow-up,” Bröckelmann said during the American Society of Hematologyopens in a new tab or window annual meeting. “We are happy to report … that most toxicities are temporary and of grade 1 and 2.”

“We need to take all of this together and [ask whether] all of our patients need anti-PD-1 blockade plus a nearly full course of chemo and radiotherapy,” he added. “This is what we want to address in the upcoming trial, looking at individualized immunotherapy in early-stage unfavorable Hodgkin lymphoma.”

A second study involving untreated early-stage unfavorable-risk or advanced classic Hodgkin lymphoma treated with pembrolizumab (Keytruda) and chemotherapy showed a PET-negative (Deauville 1-3) rate of 84% in an analysis of the first 50 patients in an ongoing trial. Treatment-related adverse events (TRAEs) were mostly grade 1/2 and more often related to the chemotherapy, reported Ranjana H. Advani, MD, of Stanford Cancer Center in California.

Bröckelmann reported updated results from the multicenter phase II NIVAHL trialopens in a new tab or window, conducted in Germany. A preliminary reportopens in a new tab or window published 2 years ago showed that all but two of 105 evaluable patients responded to nivolumab administered concurrently or sequentially with AVD (doxorubicin, vinblastine, and dacarbazine) chemotherapy. The update focused on PFS, OS, and toxicity and was published simultaneously in the Journal of Clinical Oncologyopens in a new tab or window.

The trial involved a total of 109 patients with early unfavorable classic Hodgkin lymphoma. The patients were randomly assigned to four cycles of concurrent or sequential nivolumab and AVD, followed by involved-site radiotherapy. The previously reported primary analysis showed that more than 90% of patients in each treatment arm achieved a CR by the end of treatment. Bröckelmann said no additional survival events occurred during follow-up.

The patients randomized to concurrent therapy had a 3-year PFS rate of 100%. The sequential group had a 3-year PFS rate of 98%. Both groups had a 3-year OS rate of 100%.

Minimizing Toxicity

During follow-up, three-fourths of patients had at least one adverse event (AE), most of which were grade 1/2. No patients had grade >1 cardiac events, and 95% of patients had a normal left ventricular ejection fraction. Grade 3 adverse events (AEs) occurred in 9% of patients in both arms combined (no grade 4 AEs). Only 5% of patients required corticosteroids, and a fourth of the patients required long-term non-steroid medication for AEs. At last follow-up visit, no patients required corticosteroids, and 15% remained on non-steroid medications.

Hypothyroidism was the most common grade 2 AE (21%) and also the most common nivolumab-related AE, requiring long-term medication in a majority of cases. Women accounted for almost 90% of the patients who developed hypothyroidism.

The follow-up study to NIVAHL, called INDIEopens in a new tab or window, will use the PD-1 inhibitor tislelizumab, and treatment will be driven by PET imaging. All patients will begin with two doses of tislelizumab. Patients who achieve PET-negative status at the point will receive four additional doses of the PD-1 inhibitor. Those who are not PET negative will receive four doses of tislelizumab plus chemotherapy. Involved-site radiotherapy will be reserved for patients who remain PET positive after chemotherapy.

“We want to try to get rid of most of the chemotherapy in this setting,” Bröckelmann said during the discussion that followed his talk. “We have striking early responses clinically, but also with our correlative studies, to single-agent anti-PD-1, and histologic remission is observed and also reversion of the peripheral immune landscape. We feel confident that two doses of tislelizumab can actually induce some sort of complete remission. This is the rapidly and excellently responding patient population where we can try to de-escalate.”

PET-Adapted Pembrolizumab-Chemo

Advani reported preliminary findings from the KEYNOTE-C11opens in a new tab or window study, which involved a mix of patients with newly diagnosed, early unfavorable, and advanced-stage classic Hodgkin lymphoma. Treatment consisted of pembrolizumab followed by AVD. A prior phase II studyopens in a new tab or window of the regimen showed that the median PFS or OS had yet to be reached after a median follow-up of 33 months. No disease progression or deaths had occurred, and no patient discontinued early because of toxicity.

The ongoing KEYNOTE-C11 is evaluating a PET-adapted regimen of sequential therapy with the PD-1 inhibitor plus chemotherapy, followed by pembrolizumab consolidation in early-stage unfavorable or advanced-stage classic Hodgkin lymphoma. Radiotherapy is omitted in all cases. Investigators have enrolled a total of 146 patients, and Advani presented results from a prespecified interim futility analysis involving the first 50 patients enrolled and treated.

All patients received pembrolizumab and AVD chemotherapy, followed by a PET scan. Patients who were PET negative received additional AVD. PET-positive patients received escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone) chemotherapy. All patients received pembrolizumab consolidation therapy. The 50 patients included in the interim analysis had completed all chemotherapy, 47 treated only with AVD and three who received BEACOPP.

The 146-patient study population consisted of 62 with early unfavorable disease and 84 with advanced disease, including 32 patients with bulky disease at diagnosis.

Seven of the 50 patients had PET-positive results at the end of treatment, and 42 had negative findings. The remaining patient had discontinued.

During initial pembrolizumab, 80% of the 146 patients experienced AEs: 64% had TRAEs, 12% had grade ≥3 TRAEs, and 5% discontinued because of TRAEs. Among 116 patients who received AVD, 76% had AEs of any grade, 64% had TRAEs, 54% had grade ≥3 TRAEs, and no patients discontinued.

The most common pembrolizumab-related AEs were pyrexia, pruritus, elevated alanine transaminase levels, and hyperthyroidism. Most of the AEs were grade 1/2. The most common AEs during AVD were nausea, decreased neutrophil count, and neutropenia.

“Mid-treatment, this PET-adapted regimen showed promising antitumor activity and no safety concerns,” said Advani. “Per study design, patients are continuing with planned therapy. Pembrolizumab induction followed by chemotherapy may be an effective treatment option in patients with newly diagnosed, early unfavorable, or advanced-stage classic Hodgkin lymphoma.”

Souce: Medscape

Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study.

Posted by

0


Summary

Background

Roughly 70–80% of patients with advanced stage Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin’s lymphoma.

Methods

We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin’s lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.

Findings

Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vstwo [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).

Interpretation

Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin’s lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin’s lymphoma.

Source:http://www.thelancet.com

Brentuximab vedotin doubles PFS in unfavourable-risk Hodgkin’s lymphoma after ASCT

Posted by

0


Brentuximab vedotin, the first new drug for Hodgkin’s lymphoma in more than 30 years, doubles progression-free survival (PFS) in patients with unfavourable-risk disease when used as early consolidation therapy after autologous stem cell transplantation (ASCT), the phase III AETHERA study has shown.

In patients randomized to receive brentuximab vedotin (1.8 mg/kg intravenously every 3 weeks for 16 cycles) starting 30 to 45 days after ASCT, median PFS by independent review was 42.9 months compared with 24.1 months in patients receiving placebo (hazard ratio [HR], 0.57; p=0.0013). [Lancet 2015, doi: http:dx.doi.org/10.1016/S0140-6736(15)60165-9]

“At 2 years, 63 percent of patients in the brentuximab vedotin group were progression free, compared with 51 percent in the placebo group,” said lead study author Professor Craig Moskowitz of the Memorial Sloan Kettering Cancer Centre, New York, NY, US.

“Nearly all patients who are progression free at 2 years are likely to be cured, since relapse 2 years after a transplant is unlikely,” he explained.

A consistent PFS benefit of brentuximab vedotin was observed across different subgroups of patients.

“The study met its primary endpoint. No medication available today has had such dramatic results in patients with hard-to-treat Hodgkin’s lymphoma,” said Moskowitz.

Brentuximab vedotin is an antibody-drug conjugate comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. The therapy is approved for relapsed or refractory CD30+ Hodgkin’s lymphoma in 50 countries, including Hong Kong, Japan and Singapore.

 

The antibody-drug conjugate was generally well tolerated in the AETHERA study of 329 patients with unfavourable-risk, relapsed or primary refractory classic Hodgkin’s lymphoma who had been treated with high-dose chemotherapy and ASCT. The most common side effects were peripheral sensory neuropathy (56 percent vs 16 percent with placebo) and neutropenia (35 vs 12 percent).

“AETHERA is a positive study establishing a promising new treatment approach for patients with Hodgkin’s lymphoma at high risk for relapse. However, with a PFS [rate] of about 50 percent at 24 months in the placebo group, whether this patient population is indeed high risk could be debated,” wrote Professor Andreas Engert of the Universtiy Hospital of Cologne, Germany, in a linked comment. [Lancet 2015, doi: http://dx.doi.org/10.1016/S0140-6736(15)60583-9]

“An international consortium is currently reassessing the effect of risk factors in patients with relapsed Hodgkin’s lymphoma to define a high-risk patient population in need of consolidation treatment,” he continued. “We look forward to a better definition of patients with relapsed Hodgkin’s lymphoma who should receive consolidation treatment with brentuximab vedotin.”

Although high-dose chemotherapy followed by ASCT is the standard of care for patients who relapse after or do not respond to initial chemotherapy or radiotherapy, only about 50 percent of patients are cured after ASCT. Prognosis for those who relapse after ASCT is poor, with a median PFS of 1.3 years.

NEUROLOGY QUIZ.

Posted by

0


A 55-year-old woman presented with a 2-week history of low-grade fever and holocephalic headache, which mostly resolved but were followed by a 2-week history of increasing dizziness, imbalance, and falls as well as gradual subtle mental confusion. Her medical history was significant for living related-donor renal transplantation 15 years earlier after end-stage hypertensive nephropathy.

neuro caseOther medical history included hypertension, hyperthyroidism, osteoporosis, depression, and anxiety. Social history revealed no unusual travel or animal exposures and no history of tobacco, alcohol, or recreational drug use. Medications included cyclosporine, mycophenolate mofetil, prednisone, methimazole, aripiprazole, clonazepam, bupropion hydrochloride, and zolpidem tartrate. Examination revealed abnormal mental status, with reasonably good attention but some slowness, and decreased short-term and long-term memory. Findings on cranial nerve, motor, sensory, and reflex examinations were significant only for mild resting tremor of all extremities, minimal right arm weakness, and diffuse hyperreflexia. Magnetic resonance imaging showed multiple lesions on T2-weighted fluid attenuated inversion recovery (FLAIR) imaging involving white and gray matter (Figure 1). T1-weighted images after delivery of contrast showed multiple enhancing lesions, including 2 dominant enhancing masses in the right cerebellar hemisphere and in the corpus callosum (Figure 2). Lumbar puncture revealed opening pressure of 25 cm H2O, a white blood cell count of 10/μL, a red blood cell count of 4/μL, a protein concentration of 160 mg/dL, a glucose level of 55 mg/dL (with a blood glucose level of 102 mg/dL; to convert to millimoles per liter, multiply by 0.0555), and negative cultures. The patient became increasingly lethargic and dysphagic, without systemic signs of fever or infection. Repeated computed tomographic imaging suggested increasing edema around the dominant lesions.

Posttransplant Lymphoproliferative Disorder.

 

ANSWER:

The history is of subacute symptoms mostly referable to the cerebellum but also consistent with a more central cerebral mass, as seen in the corpus callosum. Given the patient’s immunosuppression and the pronounced contrast enhancement, there was initial concern for an infectious mass or metastatic neoplasm. However, after lumbar puncture revealed only mild pleiocytosis and an elevated protein concentration as well as a normal glucose level and negative cultures, bacterial, fungal, and atypical bacterial causes seemed much less likely. There was no evidence for a primary malignant neoplasm, and the appearance of the lesions was not typical for metastatic disease. The involvement of gray matter in addition to white matter and the intense contrast enhancement made progressive multifocal leukoencephalopathy much less likely. Thus, the differential diagnosis was appropriately narrowed to posttransplant lymphoproliferative disorder vs central nervous system lymphoma. Further laboratory tests revealed active cytomegalovirus in the blood and high levels of Epstein-Barr virus genome in the cerebrospinal fluid. Bone marrow biopsy was uninformative and was negative for Epstein-Barr virus RNA. Because of her cognitive deterioration, a brain biopsy was performed. It revealed lymphohistiocytic infiltration with granuloma formation. However, in situ hybridization showed extensive presence of Epstein-Barr virus messenger RNA. All fungal and mycobacterial stains were negative. Immunophenotyping revealed a predominant T-cell population, with a subpopulation of B cells also present. There was no clear evidence for a clonal population indicative of lymphoma. A diagnosis of posttransplant lymphoproliferative disorder was made. This condition represents a polyclonal proliferative disorder related to Epstein-Barr virus infection of B cells. Typically, it occurs earlier in the course of immunosuppression but relates to the degree of immunosuppression and is typically reversible, although in some cases there may be subsequent development of frank lymphoma. Given her need for immunosuppression to retain her kidney transplant, she was given steroids and then high-dose methotrexate and rituximab. While she had some complications (including infections), she gradually improved, with mental status and gait returning to near baseline.

Source: JAMA

 

 

PET and Prognosis in Follicular Lymphoma.

Posted by

0


A negative posttreatment PET scan was associated with improved survival in patients with advanced-stage disease.

Complete remission with a negative positron emission tomography (PET) scan after front-line induction chemotherapy is associated with improved outcomes in Hodgkin lymphoma and diffuse large B-cell lymphoma. To assess the prognostic value of PET in follicular lymphoma (FL), European investigators conducted a prospective, multicenter trial involving 117 patients with advanced-stage, high–tumor burden FL who were treated with six cycles of R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) followed by two additional doses of rituximab. PET scans were performed at baseline, after cycle four (PETC4), and at completion of therapy (PETC8). Independent central review of PET response was performed by three nuclear medicine radiologists and classified by established criteria (Deauville 5-point scale). No treatment modifications were made based on PET findings.

Results were as follows:

  • Of 106 patients who underwent PETC8 imaging, 83 (78%) had negative results.
  • Of 78 patients with negative PETC4 results, 6 (8%) reverted to a positive posttreatment scan.
  • Of 26 patients with positive PETC4 results, 17 (65%) remained positive on PETC8.
  • When comparing PET response to standard computed tomography–based assessment, 53 of 54 patients (98%) with complete remissions were PET-negative, whereas 10 of 20 patients (50%) with complete remissions unconfirmed (CRu) and 9 of 26 patients (35%) with partial remission (PR) remained PET-positive.
  • Patients with negative posttreatment PET had improved 2-year overall survival versus those with a positive scan (100% vs. 88%; P=0.01).
  • Progression-free survival was improved for those with negative versus positive PETC4 or PETC8.

Comment: This is the first prospective study to demonstrate a prognostic benefit for negative posttreatment PET in FL. The predictive value was independent of both low-risk and high-risk FLIPI (Follicular Lymphoma International Prognostic Index) scores. The authors recommend that only posttreatment PET rather than interim PET be used and that scan use be reserved for CRu and PR patients. Confirmation of these results in additional prospective trials will be important, as will careful application of standardized PET response criteria and PET response–based treatment algorithms.

Source: Journal Watch Oncology and Hematology

 

Alcohol drinking, tobacco smoking and subtypes of haematological malignancy in the UK Million Women Study.

Posted by

0


Previous research suggests associations of lower alcohol intake and higher tobacco consumption with increased risks of haematological malignancy. The prospective Million Women Study provides sufficient power for reliable estimates of subtype-specific associations in women.

Methods:

Approximately 1.3 million middle-aged women were recruited in the United Kingdom during 1996–2001 and followed for death, emigration and cancer registration until 2009 (mean 10.3 years per woman); potential risk factors were assessed by questionnaire. Adjusted relative risks were estimated by Cox regression.

Results:

During follow-up, 9162 incident cases of haematological malignancy were recorded, including 7047 lymphoid and 2072 myeloid cancers. Among predominantly moderate alcohol drinkers, higher intake was associated with lower risk of lymphoid malignancies, in particular diffuse large B-cell lymphoma (relative risk 0.85 per 10 g alcohol per day (95% confidence interval 0.75–0.96)), follicular lymphoma (0.86 (0.76–0.98)) and plasma cell neoplasms (0.86 (0.77–0.96)). Among never- and current smokers, higher cigarette consumption was associated with increased risk of Hodgkin lymphoma (1.45 per 10 cigarettes per day (1.22–1.72)), mature T-cell malignancies (1.38 (1.10–1.73)) and myeloproliferative/myelodysplastic disease (1.42 (1.31–1.55)).

Conclusion:

These findings confirm and extend existing evidence for associations of subtypes of haematological malignancy with two common exposures in women.

Source: British journal of oncology