Methotrexate for Primary central nervous system lymphoma

In neurooncology and onco-hematology, intraventricular injection of chemotherapeutic agents (most typically, methotrexate) is an inevitable part of many protocols for treating patients with malignant tumors of the CNS, neuroleukemia, CNS lymphomas and some other disorders.


High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 1).


MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 2).


The addition of intraventricular MTX (rather than just intrathecal via LP) delivered through a Ommaya reservoir (6 doses of 12 mg twice a week, with IV leucovorin rescue) may result in even better survival 3)

In the event of an intrathecal MTX overdose (OD), interventions recommended 4) :

ODs of up to 85 mg can be well tolerated with little sequelae; immediate LP with drainage of CSF can remove a substantial portion of the drug (removing 15 ml of CSF can eliminate ≈ 20–30% of the MTX within 2 hrs of OD). This can be followed by ventriculolumbar perfusion over several hours using 240 ml of warmed isotonic preservative-free saline entering through the ventricular reservoir and exiting through a External lumbar cerebrospinal fluid drainage. For major OD of > 500 mg, add intrathecal administration of 2,000 U of carboxypeptidase G2 (an enzyme that inactivates MTX). In cases of MTX OD, systemic toxicity should be prevented by treating with IV dexamethasone and IV (not IT) leucovorin.


Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. 5).


A study provides Class III evidence that in immunocompetent patients with primary CNS lymphomas (PCNSLs), high-dose methotrexate (HD-MTX) plus rituximab compared with HD-MTX alone improves complete response (CR) and overall survival rates 6).

Case series

Yoon et al. presented the experiences with high-dose methotrexate (HD-MTX) monotherapy for immunocompetent patients with PCNSL at three institutions and investigate factors related to survival.

PCNSL patients, who were histologically confirmed with diffuse large B cells and treated with HD-MTX monotherapy from 2001 to 2016, were retrospectively reviewed. Patients underwent induction chemotherapy with 8 g/m2 of MTX every 10 days (maximum three cycles). Maintenance chemotherapy of 3.5 g/m2 of MTX (maximum six cycles) was selectively performed depending on the response to induction chemotherapy.

A total of 67 patients were included. Although seven patients discontinued induction chemotherapy because of MTX toxicity, 40 (59.7%) patients showed a complete response (CR) to induction chemotherapy. Twenty-six (38.8%) and three (4.5%) patients showed a CR and partial response, respectively, after maintenance chemotherapy. Forty-one patients with recurrence or progression following HD-MTX underwent second-line treatment. Progression-free survival rates were 43% and 24% at 1 and 2 years, respectively. The median overall survival was 40.3 months. In a multivariate analysis, a radiological CR to induction chemotherapy was a significant factor related to prolonged progression-free survival and overall survival (P < 0.05).

MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 7).


A single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL 8).


Zhu et al. studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. They identified 31 patients diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survivals were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 9).

References

1) , 9)

Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT. High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009 Apr;11(2):211-5. doi: 10.1215/15228517-2008-067. Epub 2008 Aug 29. PMID: 18757775; PMCID: PMC2718993.
2) , 7)

Yoon WS, Park JS, Kim YI, Chung DS, Jeun SS, Hong YK, Yang SH. High-dose methotrexate monotherapy for newly diagnosed primary central nervous system lymphoma: 15-year multicenter experience. Asia Pac J Clin Oncol. 2020 Sep 25. doi: 10.1111/ajco.13427. Epub ahead of print. PMID: 32978898.
3)

DeAngelis LM, Yahalom J, Thaler HT, Kher U. Com- bined Modality Therapy for Primary CNS Lympho- mas.JClinOncol.1992;10:635–643
4)

O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2. Mayo Clin Proc. 1996; 71:161–165
5)

Tempaku A, Takahashi Y, Kamada H. Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. Acta Haematol. 2019 May 21:1-2. doi: 10.1159/000499100. [Epub ahead of print] PubMed PMID: 31112947.
6)

Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA, Ye X. High-dose methotrexate with or without Rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014 Jul 15;83(3):235-9. doi: 10.1212/WNL.0000000000000593. Epub 2014 Jun 13. PubMed PMID: 24928128; PubMed Central PMCID: PMC4117362.
8)

Ly KI, Crew LL, Graham CA, Mrugala MM. Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience. Oncol Lett. 2016 May;11(5):3471-3476. doi: 10.3892/ol.2016.4393. Epub 2016 Mar 30. PMID: 27123138; PMCID: PMC4840907.

Thrombocytopenia

Thrombocytopenia

The terms thrombocytopenia and thrombopenia refer to a disorder in which there is a relative decrease of platelets.

These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia is a platelet count below 50,000 per microlitre.

Severe thrombocytopenia can result in petechial hemorrhages or spontaneous intracerebral hemorrhage (ICH).

Hypertension and thrombocytopenia are potentially modifiable predictors of reoperation for hematoma, which were associated greater odds of 30-day death 1).


see Heparin induced thrombocytopenia.


A free valproic acid (VPA) serum concentration of 14.67 mcg/mL had the optimal discriminating power for the occurrence of thrombocytopenia. Ammonemia should be monitored even if free VPA concentration is within the safety range 2).


Yoo et al. report the first case of severe fever with thrombocytopenia syndrome (SFTS) and a intracranial acute spontaneous subdural hematoma (SDH) in Korea. A 79-year-old male presented with fever and thrombocytopenia. On the third day of hospitalization, his mental changed from drowsy to semi-coma. Brain computed tomography indicated an acute subdural hemorrhage on the right convexity. He was given early decompressive craniectomy, but did not survive. Real-time reverse transcription polymerase chain reaction analysis of a blood sample indicated the presence of SFTS virus (SFTSV). This is the first reported case with intracranial hemorrhage and SFTS. This case report describes our treatment of a patient with acute SDH and an infection from a tick-borne species of Bunyaviridae 3).

References

1)

Dasenbrock HH, Yan SC, Chavakula V, Gormley WB, Smith TR, Claus E, Dunn IF. 145 Unplanned Reoperation After Craniotomy for Tumor: A National Surgical Quality Improvement Program Analysis. Neurosurgery. 2016 Aug;63 Suppl 1:159. doi: 10.1227/01.neu.0000489715.29455.af. PubMed PMID: 27399424.
2)

Tseng YJ, Huang SY, Kuo CH, Wang CY, Wang KC, Wu CC. Safety range of free valproic acid serum concentration in adult patients. PLoS One. 2020;15(9):e0238201. Published 2020 Sep 2. doi:10.1371/journal.pone.0238201
3)

Yoo J, Oh JW, Jang CG, Moon JH, Kim EH, Chang JH, Kim SH, Kang SG. Spontaneous Acute Subdural Hemorrhage in a Patient with a Tick Borne Bunyavirus-Induced Severe Fever with Thrombocytopenia Syndrome. Korean J Neurotrauma. 2017 Apr;13(1):57-60. doi: 10.13004/kjnt.2017.13.1.57. Epub 2017 Apr 30. PubMed PMID: 28512621; PubMed Central PMCID: PMC5432452.

Pegvisomant

Pegvisomant

Pegvisomant is a protein containing 191 amino acid residues to which several polyethylene glycol polymers have been covalently bound in order to slow clearance from the blood. The protein is a modified version of human growth hormone designed to bind to and block the growth hormone receptor. It is manufactured using genetically modified E. coli bacteria. The polyethylene glycol polymers are subsequently added chemically.

The FDA approved pegvisomant (Somavert Pfizer), a growth hormone receptor antagonist, for parenteral treatment of acromegaly in patients who are not candidates for or have had an inadequate response to surgery or other treatment 1).

As the only GH receptor antagonist (GHRA) available, pegvisomant has shown its effectiveness in the control of insulin like growth factor IGF-1 2).

van der Lely et al demonstrated Pegvisomant as an effective medical treatment for acromegaly, because of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration 3).

It is delivered as a powder that is mixed with water and injected under the skin.


Data support a comparable QoL in patients receiving pegvisomant vs. somatostatin analogue, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs 4).

Side effects

Side effects of Pegvisomant include reactions at the injection site, swelling of the limbs, chest pain, hypoglycemia, nausea and hepatitis.

Blocking of the growth hormone’s receptor reduces feedback control of the growth hormone regulation leading to approximately doubled GH levels.

The GH receptor antagonist pegvisomant is increasingly used as therapy in acromegaly.

Combination Therapy

The combination of somatostatin analog SA and pegvisomant in patients who could not achieve IGF-1 normalization was safe and aided improved quality of life in acromegaly 5) 6) 7) 8).

Further, the combination of pegvisomant and SA could reduce the dose of SA that is required 9).

There is, however, no evidence adequate to prove the significant benefits obtained from combination 10).

In Melmed et al’s guidelines, such combination is recommended on the condition that patients are resistant to other treatments 11).

In combination with cabergoline, the combination of SA and cabergoline might provide effective treatment in patients with mixed pituitary adenomas in whom simultaneously elevated prolactin (PRL) and GH are observed 12), while, in patients who are partially responsive to the maximum SA dose, additive therapy with cabergoline could normalize IGF-1 in about half of the patients, including those without prolactinemia 13).

Pituitary surgery might be indicated on pegvisomant treatment, due to side effects, adenoma growth or intention to cure after primary treatment.

1)

Pegvisomant (Somavert) for Acromegaly.The Medical Letter on Drugs and Therapeutics.1160c.45.55-56
2)

Neggers SJ, van Aken MO, de Herder WW, et al. Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant. J Clin Endocrinol Metab. 2008;93(10):3853–3859.
3)

van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, Hackett S, Zib KA, Davis RJ, Scarlett JA, Thorner MO. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001 Nov 24;358(9295):1754-9. PubMed PMID: 11734231.
4)

Dichtel LE, Kimball A, Yuen KCJ, et al. Effects of Growth Hormone Receptor Antagonism and Somatostatin Analog Administration on Quality of Life in Acromegaly [published online ahead of print, 2020 Aug 10]. Clin Endocrinol (Oxf). 2020;10.1111/cen.14309. doi:10.1111/cen.14309
5)

Fendri S, Karaca P, Tiev E, Buchfelder M, Lalau J. Control of disease activity and tumor size after introduction of pegvisomant in a lanreotide-resistant acromegalic patient. Ann Endocrinol (Paris) 2013;74(1):49–52. [PubMed]
6)

Neggers SJ, de Herder WW, Feelders RA, van der Lely AJ. Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients. Pituitary. 2011;14(3):253–258. [PMC free article] [PubMed]
7)

Madsen M, Poulsen PL, Orskov H, Møller N, Jørgensen JO. Cotreatment with pegvisomant and a somatostatin analog (SA) in SA-responsive acromegalic patients. J Clin Endocrinol Metab. 2011;96(8):2405–2413. [PubMed]
8)

van der Lely A, Bernabeu I, Cap J, et al. Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone. Eur J Endocrinol. 2011;164(3):325–333.
9) , 10)

Madsen M, Poulsen PL, Orskov H, Møller N, Jørgensen JO. Cotreatment with pegvisomant and a somatostatin analog (SA) in SA-responsive acromegalic patients. J Clin Endocrinol Metab. 2011;96(8):2405–2413.
11)

Melmed S, Colao A, Barkan A, et al. Acromegaly Consensus Group Guidelines for acromegaly management: an update. J Clin Endocrinol Metab. 2009;94(5):1509–1517.
12)

Sowiń ski J, Sawicka N, Piatek K, Zybek A, Ruchala M. Pharmacoeconomic aspects of the treatment of pituitary gland tumours. Contemp Oncol (Pozn) 2013;17(2):137–143.
13)

Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2011;96(5):1327–1335.
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