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Rituxan or Rituxan with cladribine for Variant Hairy Cell Leukemia – pro

M Levin, MD — Fri, 18 Oct 2013 14:01:45 +0000

Recent literature suggests that a subgroup of Hairy Cell Leukemia(NCL), sometimes called Variant Hairy Cell Leukemia(HCL-V)l my in fact be a different disease not related to HCL at all and which my respond to rituximab to a much higher extent than common Hairy Cell does. It is thought that this variant is what used to be called Leukemic Reticuloendotheliosis in the past. It is an uncommon disorder accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCl cases. In contrast to HCl-C, HCl-V is a more aggressive disease and according to the new WHO classification it is no longer considered to be biologically related to HCl-C. Patients with HCl-V have an elevated white blood count, easy-to-aspirate bone marrow, unlike HCL which is difficult to aspirate, and weak reactivity to tartrate – resistant acid phosphatase (TRAP). Immunophenotypically, HCl-V cells are positive for CD103 and CD11c and negative for CD25. The HCl-V cells express also the B-cell antigens, CD19, CD20 and CD22. The HCl-V patients have frequently an unmutated Ig gene configuration. Currently, the principles of therapy for this rare disease derive from uncontrolled single institutional studies, or even single case reports. In contrast to HCl-C, the HCl-V response to purine nucleoside analogs (PNA) is limited to partial responses in approximately 50% of patients. However, complete responses were observed in patients treated with rituximab and anti-CD22 immunotoxins.

For non-variant type, the use fo the first two together is based on a study reported very recently in ASCO on 3/2020 byKreitmen et al as reported in ASCO 2020. This regimen is for patients who have minimal residual disease after 6 months. In the trial, 68 patients with purine analog-naive classic hairy cell leukemia were randomly assigned to receive 0.15 mg/kg of cladribine intravenously on days 1 to 5 with eight weekly doses of rituximab at 375 mg/m2 started on day 1 (concurrent group, n = 34) or 6 months later after detection of minimal residual disease in their blood (delayed group, n = 34). Minimal residual disease tests included blood and bone marrow flow cytometry and bone marrow immunohistochemistry.

Patients in either group could receive a second course of rituximab 6 months after the first. The primary endpoint was 6-month minimal residual diseasefree complete remission rates with concurrent treatment vs cladribine monotherapy in the delayed group. THe delayed group did better nad ahd less toxicity. In the trial, 68 patients with purine analognaive classic hairy cell leukemia were randomly assigned to receive 0.15 mg/kg of cladribine intravenously on days 1 to 5 with eight weekly doses of rituximab at 375 mg/m2 started on day 1 (concurrent group, n = 34) or 6 months later after detection of minimal residual disease in their blood (delayed group, n = 34). Minimal residual disease tests included blood and bone marrow flow cytometry and bone marrow immunohistochemistry.

Patients in either group could receive a second course of rituximab 6 months after the first. The primary endpoint was 6-month minimal residual disease-free complete remission rates with concurrent treatment vs cladribine monotherapy in the delayed group, which favored the concurrent group, but with more thrmbocytopenia..
The investigators concluded: “Achieving minimal residual disease-free complete remission of hairy cell leukemia after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if minimal residual disease-free survival leads to less need for additional therapy or cure of hairy cell leukemia.”

NCCN lists single-agent cladribine or pentostatin in first line and a purine analog with rituximab for recurrent or refractory disease only. and Elitek, not in combination.

Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D, British Committee for Standards in Haematology. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol. 2012 Jan;156(2):186-95. [60 references]

Jones G, Parry-Jones N, Wilkins B, et al. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol 2012; 156:186.

Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001; 115:609.

Robak T. Current treatment options in hairy cell leukemia and hairy cell leukemia variant. Cancer Treat Rev 2006; 32:365.

Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009; 114:4687.

Robak T. Hairy-cell leukemia variant: recent view on diagnosis, biology and treatment. Cancer Treat Rev 2011; 37:3.

Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood 2017; 129:553.

https://www.ascopost.com/news/march-2020/first-line-cladribine-with-concurrent-or-delayed-rituximab-for-hairy-cell-leukemia/

nccn, hcl-1, A- 2020

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Sorafenib for desmoid tumors – pro

M Levin, MD — Mon, 17 Dec 2012 16:29:33 +0000

Desmoid tumors, also called aggressive fibromatosis, deep musculoaponeurotic fibromatosis, and fibrosarcoma grade I of the desmoid type, do not generally metastasize but can cause pain and compromise organs. Few treatments for this condition are well established, although many novel agents are being studied. Among them is Nexavar (sorafenib). The basis for the interest in this drug is that it appears to inhibit MPNST cell growth in vitro.

A recent study of sorafenib in children with neurofabromatosis was not able to establish the minmally tolerated dose. A series from Sloan Kettering used sorafenib as first-line therapy in 11/26 patients and the remaining 15/26 had received a median of 2 prior lines of therapy. Twenty-three of 26 patients had shown evidence of progressive disease by imaging, whereas 3 patients had achieved maximum benefit or toxicity with chemotherapy. Sixteen of 22 (∼70%) patients reported significant improvement of symptoms. At a median of 6 months (2-29) of treatment, the best response evaluation criteria in solid tumors (RECIST) 1.1 response included 6/24 (25%) patients with partial response (PR), 17/24 (70%) with stable disease, and 1 with progression and death. NCCN lists sorafenib on p. SARC-E and references the Goundar paper as the basis for its recommendation.

See also here for a more general discussion of chemotherapy for desmoid tumors.

Other options, see here and here and here

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CLINICAL SUMMARY:
39 year-old woman who had been treated with Doxil and experimental therapies of fibromatosis adn nwo Nexvar is being proposed.

REFERENCES:
23.Ambrosini G, Cheema HS, Seelman S, et al. Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells. Mol Cancer Ther. Apr 2008;7(4):890-6.

Kim A, Dombi E, Tepas K, Fox E, Martin S, Wolters P, Balis FM,Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas.Pediatr Blood Cancer. 2012 Sep 7.

Current Perspectives on Desmoid Tumors: The Mayo Clinic ApproachCancers 2011, 3, 3143-3155

Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res 2011; 17:4082.

nccn, Soft TIssue Sarcoma, 2012

Revlimid and Rituxan for maintenance for lymphoma – pro

M Levin, MD — Thu, 27 Sep 2012 11:52:02 +0000

Recent studies suggest that lanalidomide and rituxan are effective in relapsed or refractory lymphomas. Revlimid, in particular, shows effectiveness for maintenance in myeloma. Because both drugs are well tolerated, this created an interest in studying their effectiveness for maintenance. Currently, maintenance is not standard for most lymphomas, including Diffuse Large B Cell lymphoma. Lenalidomide alone is still in studies, for example, Maintenance Lenalidomide in Lymphoma, NCT01575860.

N. M. Reddy, R. Simmons, M. Caldwell, M. H. Jagasia, D. S. Morgan, S. I. Park, J. P. Greer, K. L. Richards; Vanderbilt University Medical Center, Nashville, TN; University of North Carolina at Chapel Hill, Chapel Hill, NC A phase II randomized study of lenalidomide or lenalidomide and rituximab as maintenance therapy following standard chemotherapy for patients with high/high-intermediate risk diffuse large B-cell lymphoma. J Clin Oncol 29: 2011 (suppl; abstr TPS138)
Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, Broccoli A, Argnani L, Pileri S, Baccarani M.
Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial.Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):462-6.

Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, Samaniego F, McLaughlin P, Fanale M, Younes A, Cabanillas F, Fowler N, Newberry KJ, Sun L, Young KH, Champlin R, Kwak L, Feng L, Badillo M, Bejarano M, Hartig K, Chen W, Chen Y, Byrne C, Bell N, Zeldis J, Romaguera J Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial.Lancet Oncol. 2012 Jul;13(7):716-23.
Eva Kimby Biological Therapy Doublets: Pairing Rituximab with Interferon, Lenalidomide, and Other Biological Agents in Patients with Follicular Lymphoma Current Hematologic Malignancy Reports September 2012, Volume 7, Issue 3, pp 221-227

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Velcade for lymphoma – pro

M Levin, MD — Thu, 21 Jun 2012 22:16:02 +0000

Bortezomib is a drug that belongs to the class of drugs called proteasome inhibitors. The proteasome is a protein complex that breaks down rusty and modified proteins that cells are meant to dispose off. Its housekeeping job is very important for the cells to keep functioning. Research studies have shown that if the proteasome is inhibited (or stopped from functioning) some cancer cells, including some lymphoma cells may find it difficult to carry out normal functions and even die. Bortezomib (Velcade) is a type of drug that inhibits proteasomes. Theoretically it can be efective in a wide spectrum of malignancies.

It has shown great results in the treatment of relapsed multiple myeloma, another type of cancer that affects the bone marrow. Trials that have tried Velcade in relapsed lymphomas over the past few years have resulted in good responses in certain types of lymphoma, especially Mantle Cell Lymphomas. Bortezomib (Velcade) has been granted approval for the treatment of relapsed or refractory Mantle Cell Lymphoma by the FDA in December 2006. It represents an important step in the approach to second-line treatments in Mantle Cell Lymphoma, a potentially difficult to treat lymphoma.

A number of trials in other lymphomas are ongoing. Phase II results of a clinical trial examining VELCADE® (bortezomib) in patients with previously untreated aggressive lymphoma were recently published in the Journal of Clinical Oncology. The study examined the efficacy of VELCADE in combination with the current standard of care (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CHOP) in 76 patients with two aggressive subtypes of lymphoma: mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL). Among 35 evaluable DLBCL patients overall response rate was 100 percent, and the complete response rate was 86 percent. There is a great interest in Velcade in a specific type of lymphoma, GCB subtype of DLBCL with the NF-κB survival pathway, which is one of the pathways known to be inhibited by VELCADE.

http://jco.ascopubs.org/content/29/25/3349.full.pdf, 2010

Schenkein D. Proteasome inhibitors in the treatment of B-cell malignancies. Clin Lymphoma. 2002;3(1):49-55.

Ruan J, Martin P, Furman RR, Lee SM, Cheung K, Vose JM, Lacasce A, Morrison J, Elstrom R, Ely S, Chadburn A, Cesarman E, Coleman M, Leonard JP.Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma.J Clin Oncol. 2011 Feb 20;29(6):690-7. Epub 2010 Dec 28.

Thalidomide or Lenalidomide and Rituximab for Mantle Cell Lymphoma – pro

M Levin, MD — Wed, 20 Jun 2012 00:29:31 +0000

Thalidomide, lenalidomide and rituximab have no direct effect on MCL cells. However, both indirectly affect peripheral blood mononuclear cell-mediated cytotoxicity, and rituximab induces both complement-dependent and antibody-dependent cellular cytotoxicity (ADCC) against MCL cells. Rituximab-induced ADCC is enhanced by lenalidomide and thalidomide. In a 2004 series, thirteen patients of sixteen enrolled (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide.Several similar studies show promise, but the combination of rituximab and thalidomide still requires investigation and is not currently recommended by any guidelines.

S.J. Richardson^{et al,}Activity of Thalidomide and Lenalidomide in Mantle Cell Lymphoma Acta Haematol 2010;123:21-29

Kaufmann H, Raderer M, Wöhrer S, Püspök A, Bankier A, Zielinski C, Chott A,Drach J. Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma.Blood. 2004 Oct 15;104(8):2269-71.

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